Papers - Sugimoto, Yoshikazu

Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation

Takahashi M., Okamoto Y., Kato Y., Shirahama H., Tsukahara S., Sugimoto Y., Tomida A.

Heliyon (Heliyon)  9 ( 4 )  2023.04

ISSN  24058440

　View Summary

Some oncoproteins along with stress kinase general control non-derepressible 2 (GCN2) can ensure the induction of activating transcription factor 4 (ATF4) to counteract amino acid deprivation; however, little is known regarding the role of the oncogenic EGFR-PI3K pathway. In this study, we demonstrate that both mutated EGFR and PIK3CA contribute to ATF4 induction following GCN2 activation in NSCLC cells. The inhibition of EGFR or PI3K mutant proteins, pharmacologically or through genetic knockdown, inhibited ATF4 induction without affecting GCN2 activation. A downstream analysis revealed that the oncogenic EGFR-PI3K pathway may utilize mTOR-mediated translation control mechanisms for ATF4 induction. Furthermore, in NSCLC cells harboring co-mutations in EGFR and PIK3CA, the combined inhibition of these oncoproteins markedly suppressed ATF4 induction and the subsequent gene expression program as well as cell viability during amino acid deprivation. Our findings establish a role for the oncogenic EGFR-PI3K pathway in the adaptive stress response and provide a strategy to improve EGFR-targeted NSCLC therapy.

• Access to Document (DOI)

Kaposi's sarcoma–associated herpesvirus replication and transcription activator protein activates CD274/PD-L1 gene promoter

Miyazawa M., Yamamoto Y., Katayama K., Sugimoto Y., Noguchi K.

Cancer Science (Cancer Science)  114 ( 4 ) 1718 - 1728 2023.04

ISSN  13479032

　View Summary

Kaposi's sarcoma–associated herpesvirus (KSHV) is responsible for the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. The expression of immunosuppressive genes, such as IL-10 and CD274/PD-L1 is observed during KSHV-associated pathogenesis, and the modulation of the host immune system by KSHV contributes to establishing viral persistence in the host. Understanding the mechanism that allows the virus to evade host cell immunity would be helpful in order to develop therapeutic strategies for KSHV malignancy. In this study, we show that KSHV replication and transcriptional activator (K-RTA), an essential activator of the viral lytic cycle, transactivates the CD274/PD-L1 gene promoter. Mechanistically, we demonstrate that the binding of K-RTA to the cellular specificity protein 1 (SP1) is critical for K-RTA–mediated CD274/PD-L1 promoter activation. These findings suggest that K-RTA cooperates with intracellular SP1 to activate the expression of CD274/PD-L1, which helps the virus regulate immune checkpoints to escape and survive.

• Access to Document (DOI)

Inhibitory Effect of Dextran Derivatives on Multidrug Resistance-Related Efflux Transporters in Vitro

Morimoto K., Ishii M., Sugimoto Y., Ogihara T., Tomita M.

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin)  45 ( 8 ) 1036 - 1042 2022.08

ISSN  09186158

　View Summary

Dextran is a promising candidate as a nanocarrier of chemotherapeutic drugs due to its biocompatibility, biodegradability, and ability to accumulate in tumors. Furthermore, dextran derivatives interact with P-glycoprotein (P-gp), so we hypothesized that they may be available as tumor-specific drug delivery systems with the ability to reverse multidrug resistance. Here, to test this idea, we investigated whether dextran and its derivatives inhibit breast cancer resistance protein (BCRP), multidrug resistance associated protein 1 (MRP1), and P-gp in vitro. First, we examined their effect on the uptake of specific fluorescent substrates by inside-out Sf-9 membrane vesicles overexpressing BCRP, MRP1, and P-gp. BCRP and MRP1 were significantly inhibited by 2-hydroxypropyl-trimethylammonium-dextran of 4 and 70kDa (Q-D4 and Q-D70) at a concentration near the clinically used concentration of dextran; however, P-gp was not inhibited. A structure–activity study showed that Q-D4, Q-D70, and 40kDa diethylaminoethyl-dextran (DEAE-D40) significantly inhibited BCRP, while 4, 40, and 70kDa dextrans (D4, D40, and D70), dextran sulfate (Sul-D40), and the individual saccharide components of dextran did not. These results suggest that the cationic side chains, but not the saccharides, are important for BCRP inhibition. Finally, cell-based efflux assay was conducted. Q-D4, Q-D70, and DEAE-D40 did not specifically increase the retention of Hoechst33342 in BCRP-overexpressing KB cells. Similarly, Q-D4 and Q-D70 did not affect the intracellular retention of specific fluorescent substrates in MRP1- and P-gp-overexpressing KB cells. The ineffectiveness in cellular systems is presumably due to inability of the dextran derivatives to access transporters located on the cytoplasmic side of the cell membrane.

• Access to Document (DOI)

Transcriptomics, molecular docking, and cross-resistance profiling of nobiletin in cancer cells and synergistic interaction with doxorubicin upon SOX5 transfection

Adham A.N., Abdelfatah S., Naqishbandi A., Sugimoto Y., Fleischer E., Efferth T.

Phytomedicine (Phytomedicine)  100 2022.06

ISSN  09447113

　View Summary

Background: Nobiletin is a polymethoxylated flavone from citrus fruit peels. Among other bioactivities, it acts antioxidative, anti-inflammatory, neuroprotective, and cardiovascular-protective. Nobiletin exerts profound anticancer activity in vitro and in vivo but the underlying mechanisms are not well understood. Purpose: The aim was to unravel the multiple modes of action against cancer cells by bioinformatic and transcriptomic techniques and their verification by molecular pharmacological methods. Methods: The in silico methods used were COMPARE analysis of transcriptomic data, signaling pathway analysis, transcription factor binding motif analysis in promoter sequences of target genes, and molecular docking. The in vitro methods used were resazurin assay, isobologram analysis, generation of stably SOX5-tranfected cells, and Western blotting. Results: Nobiletin was cytotoxic against a wide range of cell lines from different tumor types, including diverse phenotypes to established anticancer drugs (e.g., P-glycoprotein, ABCB5, p53, EGFR). Cross-resistance profiling with 83 standard anticancer drugs revealed a correlation to antihormonal anticancer drugs, which can be explained by the phytoestrogenic features of nobiletin. Transcriptomic analysis showed that the responsiveness of tumor cells was predictable by their specific mRNA expression profile. Nobiletin bound to the transcription factor SOX5 in silico. SOX5 conferred resistance to the control drug doxorubicin but collateral sensitivity to nobiletin in HEK293 cells transfected with a lentiviral GFP-tagged pLOC–ORF-SOX5 vector. The combination of nobiletin and doxorubicin synergistically killed HEK293-SOX5 cells in isobologram analyses, implying attractive new treatment options. Conclusion: Nobiletin represents an interesting candidate for cancer therapy with broad-spectrum activity and multiple modes of action. The identification of novel targets (i.e., SOX5) may allow its use for targeted tumor therapy in individualized treatment protocols.

• Access to Document (DOI)

Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML.

Yamatani K, Ai T, Saito K, Suzuki K, Hori A, Kinjo S, Ikeo K, Ruvolo V, Zhang W, Mak PY, Kaczkowski B, Harada H, Katayama K, Sugimoto Y, Myslinski J, Hato T, Miida T, Konopleva M, Hayashizaki Y, Carter BZ, Tabe T, Andreeff M.

Translational Oncology (Translational Oncology)  18   101354 2022.01

Research paper (scientific journal), Joint Work, Accepted

　View Summary

Tyrosine kinase inhibitors (TKIs) are established drugs in the therapy of FLT3-ITD mutated acute myeloid leukemia (AML). However, acquired mutations, such as D835 in the tyrosine kinase domain (FLT3-ITD/D835), can induce resistance to TKIs. A cap analysis gene expression (CAGE) technology revealed that the gene expression of BCL2A1 transcription start sites was increased in primary AML cells bearing FLT3-ITD/D835 compared to FLT3-ITD. Overexpression of BCL2A1 attenuated the sensitivity to quizartinib, a type II TKI, and venetoclax, a selective BCL2 inhibitor, in AML cell lines. However, a type I TKI, gilteritinib, inhibited the expression of BCL2A1 through inactivation of STAT5 and alleviated TKI resistance of FLT3-ITD/D835. The combination of gilteritinib and venetoclax showed synergistic effects in the FLT3-ITD/D835 positive AML cells. The promoter region of BCL2A1 contains a BRD4 binding site. Thus, the blockade of BRD4 with a BET inhibitor (CPI-0610) downregulated BCL2A1 in FLT3-mutated AML cells and extended profound suppression of FLT3-ITD/D835 mutant cells. Therefore, we propose that BCL2A1 has the potential to be a novel therapeutic target in treating FLT3-ITD/D835 mutated AML.

• Access to Document (DOI)

A novel moniliformin derivative as pan-inhibitor of histone deacetylases triggering apoptosis of leukemia cells

Lu X., Yan G., Dawood M., Klauck S.M., Sugimoto Y., Klinger A., Fleischer E., Shan L., Efferth T.

Biochemical Pharmacology (Biochemical Pharmacology)  194   114677 2021.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00062952

　View Summary

New and potent agents that evade multidrug resistance (MDR) and inhibit epigenetic modifications are of great interest in cancer drug development. Here, we describe that a moniliformin derivative (IUPAC name: 3‐(naphthalen‐2‐ylsulfanyl)‐4‐{[(2Z)‐1,3,3‐trimethyl‐2,3‐dihydro‐1H‐indol‐2‐ylidene]methyl}cyclobut‐3‐ene‐1,2‐dione; code: MCC1381) bypasses P-gp-mediated MDR. Using transcriptomics, we identified a large number of genes significantly regulated in response to MCC1381, which affected the cell cycle and disturbed cellular death and survival. The potential targets of MCC1381 might be histone deacetylases (HDACs) as predicted by SwissTargetPrediction. In silico studies confirmed that MCC1381 presented comparable affinity with HDAC1, 2, 3, 6, 8 and 11. Besides, the inhibition activity of HDACs was dose-dependently inhibited by MCC1381. Particularly, a strong binding affinity was observed between MCC1381 and HDAC6 by microscale thermophoresis analysis. MCC1381 decreased the expression of HDAC6, inversely correlated with the increase of acetylated HDAC6 substrates, acetylation p53 and α-tubulin. Furthermore, MCC1381 arrested the cell cycle at the G2/M phase, induced the generation of reactive oxygen species and collapse of the mitochondrial membrane potential. MCC1381 exhibited in vivo anti-cancer activity in xenografted zebrafish. Collectively, MCC1381 extended cytotoxicity towards P-gp-resistant leukemia cancer cells and may act as a pan-HDACs inhibitor, indicating that MCC1381 is a novel candidate for cancer therapy.

• Access to Document (DOI)

Cytotoxicity of 4-hydroxy-N-(naphthalen-1-yl)-2-oxo-2H-chromene-3-carboxamide in multidrug-resistant cancer cells through activation of PERK/eIF2α/ATF4 pathway

Lu X., Yan G., Klauck S.M., Fleischer E., Klinger A., Sugimoto Y., Shan L., Efferth T.

Biochemical Pharmacology 193   114788 2021.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00062952

• Access to Document (DOI)

2α-Hydroxyalantolactone from Pulicaria undulata: activity against multidrug-resistant tumor cells and modes of action

Hegazy M.E.F., Dawood M., Mahmoud N., Elbadawi M., Sugimoto Y., Klauck S.M., Mohamed N., Efferth T.

Phytomedicine (Phytomedicine)  81   153409 2021.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09447113

• Access to Document (DOI)

GZD824 inhibits GCN2 and sensitizes cancer cells to amino acid starvation stress

Kato Y., Kunimasa K., Takahashi M., Harada A., Nagasawa I., Osawa M., Sugimoto Y., Tomida A.

Molecular Pharmacology 98 ( 6 ) 669 - 676 2020.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0026895X

• Access to Document (DOI)

Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides

Morita T., Akiyoshi T., Sato R., Uekusa Y., Katayama K., Yajima K., Imaoka A., Sugimoto Y., Kiuchi F., Ohtani H.

Journal of Agricultural and Food Chemistry  2020.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00218561

• Access to Document (DOI)

Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses

Mahmoud N., Saeed M.E.M., Sugimoto Y., Klinger A., Fleischer E., Efferth T.

Phytomedicine (Phytomedicine)  77   153271 2020.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09447113

　View Summary

Background: Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known. Purpose: We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA. Study design: Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells. Methods: The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting. Results: Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis. Conclusion: CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.

• Access to Document (DOI)

Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells

Takahashi C., Kondo S., Sadaoka K., Ishizuka S., Noguchi K., Kato Y., Sugimoto Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  530 ( 1 ) 230 - 234 2020.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

　View Summary

JQ1 disrupts the binding of bromodomain and extra-terminal (BET) family of proteins to acetylated histones, modulates the expression of various genes, and inhibits the proliferation of cancer cells. We established two JQ1-resistant sublines from human colorectal cancer HCT116 cells. These resistant cells showed an 8- to 9-fold higher resistance to JQ1, and a 2- to 4-fold higher resistance to various anti-cancer agents, such as doxorubicin, etoposide, mitoxantrone, SN-38, cisplatin, and methotrexate than the parental HCT116 cells. The JQ1-resistant cells expressed higher levels of TRAF2 and NCK-interacting protein kinase (TNIK), cyclin D1 (CCND1), cyclin E1 (CCNE1), and their corresponding mRNAs than the parental cells. TNIK is a regulator of Wnt/β-catenin signaling and is known to transactivate CCND1. Transient transfection of HCT116 cells with a TNIK expression plasmid resulted in the upregulation of cyclin D1, cyclin E1, and their corresponding mRNAs, as well as an increase in CCNE1 promoter activity. Furthermore, luciferase assay revealed that the JQ1-resistant cells showed high CCNE1 promoter activity. These results suggest that TNIK also transactivates CCNE1. Three stable TNIK transfectant clones of HEK293 cells expressed 1.5- to 2-fold higher levels of TNIK, cyclin D1, and cyclin E1 than the parental cells. The 293/TNIK-6 cells, which expressed the highest level of TNIK among the transfectants, showed a 2.3-fold higher resistance to JQ1 than the parental cells. These results suggest the possible involvement of TNIK in cellular resistance to JQ1.

• Access to Document (DOI)

pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2

Morita T., Akiyoshi T., Sato R., Katayama K., Yajima K., Kataoka H., Imaoka A., Sugimoto Y., Ohtani H.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  35 ( 2 ) 220 - 227 2020.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  13474367

　View Summary

Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. In the present study, we evaluated the influence of pH on the OATP1A2-mediated uptake of estrone 3-sulfate using OATP1A2-expressing HEK293 cells. The uptake of 0.3 μM estrone 3-sulfate by HEK293-OATP1A2 cells was pH-dependent. OATP1A2 exhibited bimodal saturation kinetics at pH 6.3 and 7.4. Compared with that seen at pH 6.3 (5.62 μM), the Km value of the high-affinity site was 8-fold higher at pH 7.4 (43.2 μM). In addition, the influence of pH on the potency of inhibitors varied among the examined inhibitors. These results suggest that the transport properties of OATP1A2 under lower pH conditions, such as those found in the microenvironments of the small intestinal mucosa and distal tubules, differ from those seen under neutral pH conditions.

• Access to Document (DOI)

STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism

Kondo S., Kato Y., Minagawa S., Sugimoto Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  523 ( 3 ) 672 - 677 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

　View Summary

We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of STAT1 and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed STAT1 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither STAT1 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The ABCB5/STAT1 high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/STAT1 low-expressing clones. The former clones also showed a higher resistance to Glu. The STAT1-transfected clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by STAT1. These clones showed resistance to Glu and BSO, similar to the ABCB5/STAT1 high-expressing clones. The cellular glutathione levels of the STAT1-transfected clones were significantly higher than that of the control. The STAT1-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that STAT1 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove STAT1 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of STAT1.

• Access to Document (DOI)

SERCA and P-glycoprotein inhibition and ATP depletion are necessary for celastrol-induced autophagic cell death and collateral sensitivity in multidrug-resistant tumor cells

Xu S.W., Law B.Y.K., Qu S.L.Q., Hamdoun S., Chen J., Zhang W., Guo J.R., Wu A.G., Mok S.W.F., Zhang D.W., Xia C., Sugimoto Y., Efferth T., Liu L., Wong V.K.W.

Pharmacological Research (Pharmacological Research)  153   104660 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  10436618

　View Summary

Multidrug resistance (MDR) represents an obstacle in anti-cancer therapy. MDR is caused by multiple mechanisms, involving ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), which reduces intracellular drug levels to sub-therapeutic concentrations. Therefore, sensitizing agents retaining effectiveness against apoptosis- or drug-resistant cancers are desired for the treatment of MDR cancers. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump is an emerging target to overcome MDR, because of its continuous expression and because the calcium transport function is crucial to the survival of tumor cells. Previous studies showed that SERCA inhibitors exhibit anti-cancer effects in Bax-Bak-deficient, apoptosis-resistant and MDR cancers, whereas specific P-gp inhibitors reverse the MDR phenotype of cancer cells by blocking efflux of chemotherapeutic agents. Here, we unraveled SERCA and P-gp as double targets of the triterpenoid, celastrol to reverse MDR. Celastrol inhibited both SERCA and P-gp to stimulate calcium-mediated autophagy and ATP depletion, thereby induced collateral sensitivity in MDR cancer cells. In vivo studies further confirmed that celastrol suppressed tumor growth and metastasis by SERCA-mediated calcium mobilization. To the best of our knowledge, our findings demonstrate collateral sensitivity in MDR cancer cells by simultaneous inhibition of SERCA and P-gp for the first time.

• Access to Document (DOI)

Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells

Saeed M., Boulos J., Elhaboub G., Rigano D., Saab A., Loizzo M., Hassan L., Sugimoto Y., Piacente S., Tundis R., Yagi S., Khalid H., Efferth T.

Phytomedicine (Phytomedicine)  62   152945 2019.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09447113

　View Summary

Background: Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad. Purpose: This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). Methods: Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK). Results: Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins. Conclusion: CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.

• Access to Document (DOI)

Collateral sensitivity of drug-resistant ABCB5- and mutation-activated EGFR overexpressing cells towards resveratrol due to modulation of SIRT1 expression

Saeed M., Rahama M., Kuete V., Dawood M., Elbadawi M., Sugimoto Y., Efferth T.

Phytomedicine (Phytomedicine)  59   152890 2019.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09447113

　View Summary

Background: In the drug discovery field, natural products deemed a precious source of novel lead compounds. They have the ability to bypass or overcome multidrug resistance (MDR) in cancer cells. Purpose: In this study, the natural polyphenolic stilbene resveratrol (RES) has been studied for its cytotoxic activity toward MDR cancer cells. Methods: Resazurin assay was used to investigate the cytotoxicity of RES not only against a panel of drug-resistant cancer cells overexpressing P-glycoprotein/ABCB1, BCRP/ABCG2, ABCB5 (ATP-binding cassette transporters), but also mutation-activated EGFR. The assessment of proteins expression was done by Western blot analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to RES. The NF-κB activation was evaluated using NF-kB reporter cells assay. Results: Interestingly, MDR cells overexpressing ABCB5 and mutation-activated EGFR were collateral sensitive (CS) to RES. Our immunoblotting analysis highlighted that CS may be attributed to RES-induced sirtuin 1 (SIRT1) overexpression. Indeed, the SIRT1 inhibitor, sirtinol completely abolished CS to RES, indicating a causative role of SIRT1 for CS to RES. In addition, COMPARE and hierarchical cluster analyses of transcriptomic data indicated genes associated with diverse cellular mechanisms ranging from the immune response, inflammation signaling, and microtubule formation to cell migration. Searching for transcription factor binding motifs in the promoters of these genes pointed to NF-κB as one of the master regulators related to RES activity. Conclusion: The findings demonstrate that RES alone or in combination with established chemotherapeutic agents might overcome the refractory tumors. This information may be immensely useful for the development of personalized treatment.

• Access to Document (DOI)

Cytotoxicity of 40 Egyptian plant extracts targeting mechanisms of drug-resistant cancer cells

Hegazy M., Abdelfatah S., Hamed A., Mohamed T., Elshamy A., Saleh I., Reda E., Abdel-Azim N., Shams K., Sakr M., Sugimoto Y., Paré P., Efferth T.

Phytomedicine (Phytomedicine)  59   152771 2019.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09447113

　View Summary

Background: The multidrug resistance (MDR) phenotype encounters a major challenge to the success of established chemotherapy in cancer patients. We hypothesized that cytotoxic medicinal plants with novel phytochemicals can overcome MDR and kill MDR-cells with similar efficacy as drug sensitive cells. Purpose: We evaluated plant extracts from an unexplored ecosystem in Egypt with unusual climate and nutrient conditions for their activity against sensitive and multidrug-resistant cancer cell lines. Material and methods/study design: Methylene chloride: methanol (1:1) and methanol: H 2 O (7:3) extracts of 40 plants were prepared resulting in a sum of 76 fraction containing compounds with varying polarity. The resazurin reduction assay was employed to evaluate the cytotoxicity of these extracts on five matched pairs of drug-sensitive and their drug-resistant cell lines. Flow cytometry and Western blotting was used to determine cell cycle analyses, apoptosis, and autophagy. Reactive oxygen species (ROS) were measured spectrophotometrically. Results: Extracts derived from Withania obtusifolia (WO), Jasonia candicans (JC), Centaurea lippii (CL), and Pulicaria undulata (PU) were the most active ones among 76 extracts from 40 Egyptian medicinal plants. They showed a significant reduction of cell viability on drug-sensitive CCRF-CEM leukemia cell line with IC 50 values less than 7 µg/ml. Low cross-resistance degrees were observed in multidrug-resistant CEM/ADR5000 cells towards CL (1.82-fold) and JC (6.09-fold). All other drug-resistant cell lines did not reveal cross-resistance to the four extracts. Further mechanistic assessment have been studied for these four extracts. Conclusion: The methylene chloride: methanol (1:1) fractions of WO, JC, CL, and PU are promising cytotoxic extracts that could be used to combat MDR cancer cells through different cell death pathways.

• Access to Document (DOI)

Novel pharmacological effects of poly (ADP-ribose) polymerase inhibitor rucaparib on the lactate dehydrogenase pathway

Nonomiya Y., Noguchi K., Katayama K., Sugimoto Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  510 ( 4 ) 501 - 507 2019.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

　View Summary

Poly (ADP-ribose) polymerases (PARPs) are involved in various cellular events, including DNA repair. PARP inhibitors including olaparib and rucaparib, have been specially developed against breast and ovarian cancers deficient in DNA repair systems. In this study, we found that PARP1-defective olaparib-resistant A2780 cells (ola-R cells) cells were still sensitive to two PARP inhibitors, rucaparib and veliparib. Metabolomic analysis revealed that rucaparib suppressed the lactate dehydrogenase (LDH)-mediated conversion of pyruvic acid to lactic acid in A2780 cells, although olaparib did not. The inhibition of LDH by siRNA-mediated knockdown or by LDH inhibitors suppressed the growth of ovarian cancer cells. Our results suggested that the suppression of the LDH-associated pathway contributed to the pharmacological effects of rucaparib.

• Access to Document (DOI)

Synthesis of 5-Hydroxy-3′,4′,7-trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2-Mediated Anticancer Drug Resistance

Tsunekawa R., Katayama K., Hanaya K., Higashibayashi S., Sugimoto Y., Sugai T.

ChemBioChem (ChemBioChem)  20 ( 2 ) 210 - 220 2019.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  14394227

　View Summary

3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI 50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI 50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

• Access to Document (DOI)

SNAIL- and SLUG-induced side population phenotype of HCT116 human colorectal cancer cells and its regulation by BET inhibitors

Kato Y., Kondo S., Itakura T., Tokunaga M., Hatayama S., Katayama K., Sugimoto Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  521 ( 1 ) 152 - 157 2019

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

　View Summary

Epithelial-mesenchymal transition (EMT) is associated with cancer malignancies such as invasion, metastasis, and drug resistance. In this study, HCT116 human colorectal cancer cells were transduced with SLUG or SNAIL retroviruses, and EMT cells with mesenchymal morphology were established. The EMT cells showed a high invasive activity and resistance to several anticancer agents such as methotrexate, SN-38, and cisplatin. Furthermore, they contained about 1–10% side population (SP) cells that were not stained by Hoechst 33342. This SP phenotype was not stable; the isolated SP cells generated both SP and non-SP cells, suggesting a potential for differentiation. Gene expression analysis of SP cells suggested the alteration of genes that are involved in epigenetic changes. Therefore, we examined the effect of 74 epigenetic inhibitors, and found that two inhibitors, namely I-BET151 and bromosporine, targeting the bromodomain and extra-terminal motif (BET) proteins, decreased the ratio of SP cells to <50% compared with the control, without affecting the immediate efflux of Hoechst 33342 by transporters. In addition, compared with the parental cells, the EMT cells showed a higher sensitivity to I-BET151 and bromosporine. This study suggests that EMT development and SP phenotype can be independent events but both are regulated by BET inhibitors in SLUG- or SNAIL-transducted HCT116 cells.

• Access to Document (DOI)

Regorafenib-induced hand-foot skin reaction is more severe on the feet than on the hands

Nonomiya Y., Yokokawa T., Kawakami K., Kobayashi K., Aoyama T., Takiguchi T., Sugisaki T., Suzuki K., Suenaga M., Wakatsuki T., Yamaguchi K., Sugimoto Y., Hama T.

Oncology Research (Oncology Research)  27 ( 5 ) 551 - 556 2019

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09650407

　View Summary

Regorafenib is a multikinase inhibitor for the treatment of metastatic colorectal cancer. Regorafenib-induced hand-foot skin reaction (HFSR) is a common side effect during treatment. The reported frequency of HFSR was 80% (grade 3: 28%) in the Japanese subpopulation in the CORRECT trial; however, more detailed data regarding HFSR in terms of onset and sites of susceptibility are unclear. Additionally, the risk factors for regorafenib-induced severe HFSR are unknown. The aim of this study was to compare HFSR between the hands and feet and identify preexisting risk factors for severe HFSR in Japanese patients receiving regorafenib. We retrospectively examined the onset and severity of HFSR on the hands and feet of patients with metastatic colorectal cancer treated with regorafenib from May 2013 to October 2015 in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. In addition, we examined the possible association between preexisting clinical factors and severe HFSR. Our results showed that no significant difference in the incidence of HFSR of any grade was observed between the hands (71%) and feet (74%) (p=0.63). The incidence of grade 3 HFSR was more frequent on the feet (33%) than on the hands (8%) (p<0.01). The onset of grade 3 HFSR was earlier on the feet than on the hands (p<0.001). No preexisting risk factor was identified. Our findings indicate that severe HFSR was more prevalent on the feet than on the hands, suggesting the need for appropriate screening for early detection and treatment of regorafenib-induced HSFR.

• Access to Document (DOI)

Cytotoxicity of sesquiterpene alkaloids from Nuphar plants toward sensitive and drug-resistant cell lines.

Fukaya M, Nakamura S, Hegazy MEF, Sugimoto Y, Hayashi N, Nakashima S, Yoshikawa M, Efferth, Matsuda H.

Food and Function (Food and Function)  9 ( 12 ) 6279 - 6286 2018.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  20426496

　View Summary

Multi-drug resistance (MDR) is a critical problem in cancer chemotherapy. MDR causes the overexpression of ATP-binding cassette (ABC) transporters and mutations in tumor suppressor genes and oncogenes. To tackle this issue, in this study, we focused on Nuphar plants, which have been traditionally used as food. Sesquiterpene alkaloids (1-3) were isolated from N. japonicum and dimeric sesquiterpene thioalkaloids (4-10) were isolated from N. pumilum. P-glycoprotein-overexpressing CEM/ADR5000 cells were cross-resistant to 6,6′-dihydroxythiobinupharidine (10). Using in silico molecular docking, we calculated the binding energies and simulated the interactions of these compounds with the corresponding amino acid residues at the binding site of P-gp. In addition, we investigated the cytotoxicity of these compounds towards cell lines overexpressing other ABC transporters (BCRP, ABCB5), cell lines with a knocked out tumor suppressor gene TP53 or cell lines overexpressing a deletion-activated EGFR oncogene. These cell lines were sensitive or only minimally cross-resistant to these compounds compared with their corresponding wild-type cell lines.

• Access to Document (DOI)

Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation.

Mahmoud N, Saeed MEM, Sugimoto Y, Klauck SM, Greten HJ, Efferth T.

Oncotarget (Oncotarget)  9 ( 87 ) 35762 - 35779 2018.11

Research paper (scientific journal), Joint Work, Accepted

　View Summary

Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (ABCB1, ABCG2, ABCB5, TP53, EGFR) were evaluated against nimbolide. The P-glycoprotein (ABCB1/MDR1)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in ABCB1/MDR1 mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor TP53 did not correlate to nimbolide's activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide's activity. Interestingly, HIF1α was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.

• Access to Document (DOI)

BCR-ABL tyrosine kinase inhibition induces metabolic vulnerability by preventing the integrated stress response in K562 cells.

Kato Y, Kunimasa K, Sugimoto Y, Tomida A.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  504 ( 4 ) 721 - 726 2018.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

　View Summary

The integrated stress response (ISR) is a cellular process that is characterized by activation of eukaryotic initiation factor (eIF)2α kinases and subsequent induction of activating transcription factor (ATF)4. The ISR plays an important role in protecting cells from tumor-related metabolic stresses, such as nutrient deprivation and perturbed proteostasis. Here, we showed that disruption of the ISR, together with increased cellular stress vulnerability, was produced by pharmacological inhibition of BCR-ABL, the oncogenic driver in chronic myeloid leukemia (CML). Treatment of CML-derived K562 cells with BCR-ABL tyrosine kinase inhibitors, including imatinib, dasatinib, nilotinib and ponatinib, prevented activation of eIF2α kinases, protein kinase-like endoplasmic reticulum kinase (PERK) and general control nonderepressible 2, and downstream ATF4 induction during metabolic stress. Prevention of ATF4 induction likely occurred as a result of the combinatorial suppression of the eIF2α kinase and phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathways. In addition, we found that pharmacological inhibition of PERK mimicked BCR-ABL inhibition to enhance apoptosis induction under stress conditions. These findings indicate that the ISR is under the control of BCR-ABL and may foster adaptation to tumorigenic stresses in CML cells.

• Access to Document (DOI)

Repurposing of Bromocriptine for Cancer Therapy.

Seo EJ, Sugimoto Y, Greten HJ, Efferth T.

Front Pharmacol (Frontiers in Pharmacology)  9 ( OCT ) 1030 2018.10

Research paper (scientific journal), Joint Work, Accepted

　View Summary

© 2007 - 2018 Frontiers Media S.A. All Rights Reserved. Bromocriptine is an ergot alkaloid and dopamine D2 receptor agonist used to treat Parkinson's disease, acromegaly, hyperprolactinemia, and galactorrhea, and more recently diabetes mellitus. The drug is also active against pituitary hormone-dependent tumors (prolactinomas and growth-hormone producing adenomas). We investigated, whether bromocriptine also inhibits hormone-independent and multidrug-resistant (MDR) tumors. We found that bromocriptine was cytotoxic towards drug-sensitive CCRF-CEM, multidrug-resistant CEM/ADR5000 leukemic cells as well as wild-type or multidrug-resistant ABCB5-transfected HEK293 cell lines, but not sensitive or BCRP-transfected multidrug-resistant MDA-MB-231 breast cancer cells. Bromocriptine strongly bound to NF-κB pathway proteins as shown by molecular docking and interacted more strongly with DNA-bound NF-κB than free NF-κB, indicating that bromocriptine may inhibit NF-κB binding to DNA. Furthermore, bromocriptine decreased NF-κB activity by a SEAP-driven NF-κB reporter cell assay. The expression of MDR-conferring ABC-transporters (ABCB1, ABCB5, ABCC1, and ABCG2) and other resistance-mediating factors (EGFR, mutated TP53, and IκB) did not correlate with cellular response to bromocriptine in a panel of 60 NCI cell lines. There was no correlation between cellular response to bromocriptine and anticancer drugs usually involved in MDR (e.g., anthracyclines, Vinca alkaloids, taxanes, epipodophyllotoxins, and others). COMPARE analysis of microarray-based mRNA expression in these cell lines revealed that genes from various functional groups such as ribosomal proteins, transcription, translation, DNA repair, DNA damage, protein folding, mitochondrial respiratory chain, and chemokines correlated with cellular response to bromocriptine. Our results indicate that bromocriptine inhibited drug-resistant tumor cells with different resistance mechanisms in a hormone-independent manner. As refractory and otherwise drug-resistant tumors represent a major challenge to successful cancer chemotherapy, bromocriptine may be considered for repurposing in cancer therapy.

• Access to Document (DOI)

Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells.

Fujiwara C, Muramatsu M, Nishii M, Tokunaka K, Tahara H, Ueno M, Yamori T, Sugimoto Y, Seimiya H.

Sci Rep (Scientific Reports)  8 ( 1 ) 14827 2018.10

Research paper (scientific journal), Joint Work, Accepted

　View Summary

© 2018, The Author(s). Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks. Telomere elongation and lamin A overexpression attenuated telomeric and non-telomeric DNA damage, respectively, and both conferred resistance to apoptosis induced by MST-312 and other DNA damaging anticancer agents. These observations suggest that sufficient pools of telomeres and a nuclear lamina component contribute to the cellular robustness against DNA damage induced by therapeutic treatment in human cancer cells.

• Access to Document (DOI)

Heat shock protein 90 inhibitors overcome the resistance to Fms-like tyrosine kinase 3 inhibitors in acute myeloid leukemia.

Katayama K, Noguchi K, Sugimoto Y.

Oncotarget (Oncotarget)  9 ( 76 ) 34240 - 34258 2018.09

Research paper (scientific journal), Joint Work, Accepted

　View Summary

© 2018 Aksenova et al. Internal tandem duplication (ITD) in Fms-like tyrosine kinase 3 (FLT3) is frequently observed in acute myeloid leukemia (AML). Quizartinib, gilteritinib, and midostaurin are inhibitors against FLT3-ITD that have good efficacy for FLT3-ITD-positive AML patients. Long-term administration leads to drug resistance through acquired tyrosine kinase domain (TKD) mutations in FLT3-ITD, such as N676K, F691L, D835V, and Y842C. Here, our screen to detect inhibitors capable of overcoming resistance to FLT3 inhibitors identified heat shock protein (HSP) 90 inhibitors as potential candidates. Although Ba/F3 cells expressing FLT3-ITD with TKD mutations (Ba/F3-ITD+N676K, Ba/F3-ITD+F691L, Ba/F3-ITD+D835V, and Ba/F3-ITD+Y842C) showed various resistance patterns to FLT3 inhibitors compared with Ba/F3-ITD cells that express FLT3-ITD lacking TKD mutations, they were more sensitive to HSP90 inhibitors than Ba/F3 cells. Notably, the Ba/F3-ITD+D835V cells were the most sensitive to HSP90 inhibitors. Treatment with HSP90 inhibitors downregulated FLT3 and its downstream signaling and induced G1 arrest followed by apoptosis in Ba/F3-ITD+N676K, Ba/F3-ITD+F691L, Ba/F3-ITD+Y842C, and especially Ba/F3-ITD+D835V cells at lower concentrations compared with Ba/F3-ITD cells. The downregulation of FLT3-ITD+D835V was caused by rapid proteolysis in autophagy. Similar results were also observed in the quizartinib-resistant MV4-11 cells, QR1 and QR2, which were established by culturing cells in the presence of quizartinib and harbored FLT3-ITD+D835H and FLT3-ITD+D835V, respectively, in a single allele. Interestingly, the efficacies of HSP90 inhibitors in QR cells are reversely correlated with that of quizartib, but not to gilteritinib and midostaurin. Collectively, HSP90 inhibitors are good candidates to overcome drug resistance in AML with various FLT3-ITD TKD mutations.

• Access to Document (DOI)

Protein kinase C alpha-mediated phosphorylation of PIM-1L promotes the survival and proliferation of acute myeloid leukemia cells.

Takami M, Katayama K, Noguchi K, Sugimoto Y.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications)  503 ( 3 ) 1364 - 1371 2018.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006291X

　View Summary

© 2018 Elsevier Inc. FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) is a constitutively active mutant of FLT3 and causes 20%–30% of acute myeloid leukemia (AML) cases. FLT3-ITD upregulates the proviral integration site for Moloney murine leukemia virus 1 (PIM-1) expression and promotes the proliferation of AML cells. In this study, we investigated the role of protein kinase C (PKC)-mediated phosphorylation on the expression and function of PIM-1L. Drug screening in leukemia cell lines revealed that sotrastaurin (a PKC inhibitor) suppressed the proliferation of the FLT3-ITD-positive AML cell line MV4-11 but not of K562, HL60, or KG-1a cells, similar to SGI-1776 (a PIM-1/FLT3 inhibitor) and quizartinib (an FLT3 inhibitor). Sotrastaurin decreased the expression of pro-survival protein myeloid cell leukemia (MCL-1) and the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), both of which are downstream effectors of PIM-1. PKCα directly phosphorylated Ser65 of PIM-1L, which is a long isoform of PIM-1. The PKCα-mediated phosphorylation stabilized PIM-1L. The phosphorylation-mimicked mutant, PIM-1L-S65D, was more stable and showed higher kinase activity than PIM-1L-S65A. Expression of PIM-1L-wildtype or -S65D reduced sotrastaurin-mediated apoptosis and growth inhibition in MV4-11 transfectants. These results suggest that PKCα directly upregulates PIM-1L, resulting in promotion of the survival and proliferation of AML cells.

• Access to Document (DOI)

Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR).

Saeed MEM, Mahmoud N, Sugimoto Y, Efferth T, Abdel-Aziz H.

Front Pharmacol (Frontiers in Pharmacology)  9 ( MAY ) 481 2018.05

Research paper (scientific journal), Joint Work, Accepted

　View Summary

© 2018 Saeed, Mahmoud, Sugimoto, Efferth and Abdel-Aziz. Betulinic acid (BetA) is a naturally occurring pentacyclic triterpene isolated from the outer bark of white-barked birch trees and many other medicinal plants. Here, we studied betulinic acid's cytotoxic activity against drug-resistant tumor cell lines. P-glycoprotein (MDR1/ABCB1) and BCRP (ABCG2) are known ATP-binding cassette (ABC) drug transporters that mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. Constitutive activation of the EGF receptor is tightly linked to the development of chemotherapeutic resistance. BetA inhibited P-gp, BCRP, ABCB5 and mutation activated EGFR overexpressing cells with similar efficacy as their drug-sensitive parental counterparts. Furthermore, the mRNA expressions of ABCB1, BCRP, ABCB5 and EGFR were not related to the 50% inhibition concentrations (IC50) for BetA in a panel of 60 cell lines of the National Cancer Institute (NCI), USA. In addition to well-established MDR mechanisms, we attempted to identify other molecular mechanisms that play a role in mediating BetA's cytotoxic activity. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell lines panel. Various genes significantly correlating to BetA's activity were involved in different biological processes, e.g., cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination and proteasome degradation. Immunoblotting and in silico analyses revealed that the inhibition of AMFR activity might be one of the mechanisms for BetA to overcome MDR phenotypes. In conclusion, BetA may have therapeutic potential for the treatment of refractory tumors.

• Access to Document (DOI)

Molecular Determinants of Sensitivity or Resistance of Cancer Cells Toward Sanguinarine.

Saeed MEM, Mahmoud N, Sugimoto Y, Efferth T, Abdel-Aziz H.

Front Pharmacol (Frontiers in Pharmacology)  9 ( FEB ) 136 2018.02

Research paper (scientific journal), Joint Work, Accepted

　View Summary

© 2018 Saeed, Mahmoud, Sugimoto, Efferth and Abdel-Aziz. For decades, natural products represented a significant source of diverse and unique bioactive lead compounds in drug discovery field. In Clinical oncology, complete tumors remission is hampered by the development of drug-resistance. Therefore, development of cytotoxic agents that may overcome drug resistance is urgently needed. Here, the natural benzophenanthridine alkaloid sanguinarine has been studied for its cytotoxic activity against multidrug resistance (MDR) cancer cells. We investigated the role of the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5 in drug resistance. Further drug resistance mechanisms analyzed in this study were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). Multidrug resistant cells overexpressing BCRP, ABCB5 and mutated ΔEGFR were not cross-resistant toward sanguinarine. Interestingly, P-gp overexpressing cells were hypersensitive to sanguinarine. Doxorubicin uptake assay carried by flow cytometry revealed that sanguinarine is a potent inhibitor of the P-gp transporter. Moreover, immunoblotting analysis proved that P-gp was downregulated in a dose dependent manner after treating P-gp overexpressing cells with sanguinarine. It was surmised that The inhibition of NFκB activity might explain the collateral sensitivity in CEM/ADR5000 cells. The COMPARE and hierarchical cluster analyses of transcriptome-wide expression profiles of tumor cell lines of the National Cancer Institute identified genes involved in various cellular processes (immune response, inflammation signaling, cell migration and microtubule formation) significantly correlated with log10IC50 values for sanguinarine. In conclusion, sanguinarine may have therapeutic potential for treating multidrug resistant tumors.

• Access to Document (DOI)

IL-10 promoter transactivation by the viral K-RTA protein involves the host-cell transcription factors, specificity proteins 1 and 3.

Miyazawa M, Noguchi K, Kujirai M, Katayama K, Yamagoe S, Sugimoto Y.

J Biol Chem (Journal of Biological Chemistry)  293 ( 2 ) 662 - 676 2018.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00219258

　View Summary

© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (HHV-8) causes a persistent infection, presenting latent and lytic replication phases during its life cycle. KSHVrelated diseases are associated with deregulated expression of inflammatory cytokines, including IL-6 and IL-10, but the mechanisms underlying this dysregulation are unclear. Herein, we report a molecular mechanism for KSHV-induced IL-10 gene expression. KSHV replication and transcription activator (K-RTA) is a molecular switch for the initiation of expression of viral lytic genes, and we describe, for the first time, that K-RTA significantly activates the promoter of the human IL-10 gene. Of note, mutations involving a basic region of K-RTA reduced the association of K-RTA with the IL-10 promoter. Moreover, the host-cell transcription factors, specificity proteins (SP) 1 and 3, play a pivotal cooperative role in K-RTA-mediated transactivation of the IL-10 promoter. K-RTA can interact with SP1 and SP3 directly in vitro, and electrophoresis mobility shift assays (EMSAs) revealed co-operative interaction involving K-RTA, SP1, and SP3 in binding to the IL-10 promoter. As DNase I footprinting assays indicated that K-RTA did not affect SP3 binding to the IL-10 promoter, SP3 can function to recruit K-RTA to the IL-10 promoter. These findings indicate that K-RTA can directly contribute to IL-10 up-regulation via a functional interplay with the cellular transcription factors SP1 and SP3.

• Access to Document (DOI)

mTOR signaling mediates resistance to tankyrase inhibitors in Wnt-driven colorectal cancer.

Mashima T, Taneda Y, Jang MK, Mizutani A, Muramatsu Y, Yoshida H, Sato A, Tanaka N, Sugimoto Y, Seimiya H.

Oncotarget 8 ( 29 ) 47902 - 47915 2017.07

Research paper (scientific journal), Joint Work, Accepted

• Access to Document (DOI)

APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer.

Tanaka N, Mashima T, Mizutani A, Sato A, Aoyama A, Gong B, Yoshida H, Muramatsu Y, Nakata K, Matsuura M, Katayama R, Nagayama S, Fujita N, Sugimoto Y, Seimiya H.

Mol Cancer Ther 16 ( 4 ) 752 - 762 2017.04

Research paper (scientific journal), Joint Work, Accepted

• Access to Document (DOI)

RSK1 protects P-glycoprotein/ABCB1 against ubiquitin-proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2R1.

Katayama K, Fujiwara C, Noguchi K, Sugimoto Y.

Sci Rep  2016

Research paper (scientific journal), Joint Work, Accepted

• Access to Document (DOI)

Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.

Nonomiya Y, Noguchi K, Tanaka N, Kasagaki T, Katayama K, Sugimoto Y.

Cancer Sci 107 ( 12 ) 1877 - 1887 2016

Research paper (scientific journal), Joint Work, Accepted

• Access to Document (DOI)

Functional effects of AKT3 on aurora kinase inhibitor-induced aneuploidy

Noguchi K, Hongama K, Hariki S, Nonomiya Y, Katayama K, Sugimoto Y.

J Biol Chem  2016

Research paper (scientific journal), Joint Work

• Access to Document (DOI)

Upregulation of cellular glutathione levels in human ABCB5- and murine Abcb5-transfected cells.

Kondo S, Hongama K, Hanaya K, Yoshida R, Kawanobe T, Katayama K, Noguchi K, Sugimoto Y

BMC Pharmacol Toxicol. 16   37 2015.12

Research paper (scientific journal), Joint Work, Accepted

Cytotoxicity of 35 medicinal plants from Sudan towards sensitive and multidrug-resistant Cancer cells.

Saeed ME, Abdelgadir H, Sugimoto Y, Khalid HE, Efferth T

J Ethnopharmacol 174   644 - 658 2015.11

Research paper (scientific journal), Joint Work, Accepted

Cytotoxicity of the sesquiterpene lactones neoambrosin and damsin from Ambrosia maritima against multidrug-resistant cancer cells.

Saeed M, Jacob S, Sandjo, L, Sugimoto Y, Khalid H, Opatz T, Thines T, Efferth T

Front. Pharmacology 6   267 2015.11

Research paper (scientific journal), Joint Work, Accepted

Regulations of P-Glycoprotein/ABCB1/MDR1 in Human Cancer Cells

Katayama K, Noguchi K, Sugimoto Y.

New Journal of Science (Hindawi Publishing Corporation)  2014   476974 2015.05

Research paper (scientific journal), Joint Work, Accepted

Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

Saeed M, Kadioglu O, Khalid H, Sugimoto Y, Efferth T.

J Nutr Biochem. (Elsevier)  26 ( 1 ) 44 - 56 2015.01

Research paper (scientific journal), Joint Work, Accepted

Suppression of γ-irradiation-induced deletion mutations under Parp-1 deficiency in mice.

Wang J, Abe M, Sasamoto E, Maeda D, Sugimoto Y, Miki Y, Masutani M.

Scholars Acad J Biosci 3 ( 12 ) 998 - 1004 2015

Research paper (scientific journal), Joint Work, Accepted

Resistance mechanisms of cancer cells to the novel vacuolar H+-ATPase inhibitor archazolid B.

Hamm R, Sugimoto Y, Steinmetz H, Efferth T.

Invest New Drugs (Springer)  32 ( 5 ) 893 - 903 2014.10

Research paper (scientific journal), Joint Work, Accepted

The lignan, (-)-sesamin reveals cytotoxicity toward cancer cells: pharmacogenomic determination of genes associated with sensitivity or resistance.

Saeed M, Khalid H, Sugimoto Y, Efferth T.

Phytomedicine (Elsevier)  21 ( 5 ) 689 - 696 2014.04

Research paper (scientific journal), Joint Work, Accepted

Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function.

Katayama K, Yamaguchi M, Noguchi K, Sugimoto Y.

Cancer Letters 345 ( 1 ) 124 - 131 2014.04

Research paper (scientific journal), Joint Work, Accepted

Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function.

Katayama K, Yamaguchi M, Noguchi K, Sugimoto Y*.

Cancer Letters 345   p 124-131 2014.04

Research paper (scientific journal), Joint Work, Accepted

The lignan, (-)-sesamin reveals cytotoxicity toward cancer cells: Pharmacogenomic determination of genes associated with sensitivity or resistance.

Saeed M, Khalid H, Sugimoto Y, Efferth T.

Phytomedicine 21(5)   689-696 2014.04

Research paper (scientific journal), Joint Work, Accepted

Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics.

Noguchi K, Katayama K, Sugimoto Y.

Pharmacogenomics and Personalized Medicine 7   53 - 64 2014.02

Research paper (scientific journal), Accepted

Biochemical Interaction of Anti-HCV Telaprevir with the ABC Transporters P-glycoprotein and Breast Cancer Resistance Protein.

Fujita Y, Noguchi K*, Suzuki T, Katayama K, Sugimoto Y.

BMC Research Notes 6   445 2013.11

Research paper (scientific journal), Joint Work, Accepted

FBXO15 regulates P-glycoprotein/ABCB1 expression through the ubiquitin-proteasome pathway in cancer cells.

Katayama K, Noguchi K, Sugimoto Y*.

Cancer Science 104   694-702 2013.06

Research paper (scientific journal), Joint Work, Accepted

Human decidua-derived mesenchymal cells is a promising source for generation and cell banking of human induced pluripotent stem cells.

Shofuda T, Kanematsu D, Fukusumi H, Yamamoto A, Bamba Y, Yoshitatsu S, Suemizu H, Nakamura M, Sugimoto Y, Furue M, Kohara A, Akamatsu W, Okada Y, Okano H, Yamasaki M, Kanemura Y*.

Cell Medicine 4(3)   125-147 2013.05

Research paper (scientific journal), Joint Work, Accepted

Expression of human ABCB5 confers resistance to taxanes and anthracyclines.

Kawanobe T, Kogure S, Nakamura S, Sato M, Katayama K, Mitsuhashi J, Noguchi K, Sugimoto Y*.

Biochemical and Biophysical Research Communications 418   736-41 2012.03

Research paper (scientific journal), Joint Work, Accepted

Novel regulatory role for Kaposi's sarcoma-associated herpesvirus-encoded vFLIP in chemosensitization to bleomycin.

Masuda Y, Noguchi K*, Segawa H, Tanaka N, Katayama K, Mitsuhashi J, Sugimoto Y.

Biochemical and Biophysical Research Communications 415   305-12 2011.12

Research paper (scientific journal), Joint Work, Accepted

DNA ligand designed to antagonize EBNA1 represses Epstein-Barr virus-induced immortalization.

Yasuda A, Noguchi K*, Minoshima M, Kashiwazaki G, Kanda T, Katayama K, Mitsuhashi J, Bando T, Sugiyama H, Sugimoto Y.

Cancer Science 102   2221-30 2011.12

Research paper (scientific journal), Joint Work, Accepted

Novel acrylonitrile derivatives, YHO-13177 and YHO-13351, reverse BCRP/ABCG2-mediated drug resistance in vitro and in vivo.

Yamazaki R*, Nishiyama Y, Furuta T, Hatano H, Igarashi Y, Kodaira H, Takahashi H, Aiyama R, Matsuzaki T, Yagi N, Sugimoto Y.

Molecular Cancer Therapeutics 10(7)   1252-1263 2011.07

Research paper (scientific journal), Joint Work, Accepted

BCRP/ABCG2 confers anticancer drug resistance without covalent dimerization.

Shigeta J, Katayama K, Mitsuhashi J, Noguchi K, Sugimoto Y*.

Cancer Science 101   1813-1821 2010.08

Research paper (scientific journal), Joint Work, Accepted

In vivo expansion of MDR1-transduced cells accompanied by a post-transplantation chemotherapy regimen with mitomycin C and methotrexate.

Mitsuhashi J, Hosoyama H, Tsukahara S, Katayama K, Noguchi K, Ito Y, Hatake K, Aiba K, Takahashi S, Sugimoto Y*.

Journal of Gene Medicine 12   596-603 2010.07

Research paper (scientific journal), Joint Work, Accepted

Pharmacological interaction with sunitinib is abolished by a germ line mutation (1291T>C) of BCRP/ABCG2 gene.

Kawahara H, Noguchi K, Katayama K, Mitsuhashi J, Sugimoto Y*.

Cancer Sci 101(6)   1493-1500 2010.06

Research paper (scientific journal), Joint Work, Accepted

Functional availability of gamma-herpesvirus K-cyclin is regulated by cellular CDK6 and p16INK4a.

Yoshioka H, Noguchi K, Katayama K, Mitsuhashi J, Yamagoe S, Fujimuro M, Sugimoto Y*.

Biochem Biophys Res Commun 394(4)   1000-1005 2010.03

Research paper (scientific journal), Joint Work, Accepted

A novel yeast cell-based screening identifies flavone as a tankyrase inhibitor.

Yashiroda Y, Okamoto R, Hatsugai K, Takemoto Y, Goshima N, Saito T, Hamamoto M, Sugimoto Y, Osada H, Seimiya H, Yoshida M*.

Biochem Biophys Res Commun 394(3)   569-573 2010.03

Research paper (scientific journal), Joint Work, Accepted

Breast cancer resistance protein (BCRP) is a molecular determinant of the outcome of photodynamic therapy (PDT) for centrally located early lung cancer.

Usuda J*, Tsunoda Y, Ichinose S, Ishizumi T, Ohtani K, Maehara S, Ono S, Tsutsui H, Ohira T, Okunaka T, Furukawa K, Sugimoto Y, Kato H, Ikeda N.

Lung Cancer 67   198-204 2010.02

Research paper (scientific journal), Joint Work, Accepted

Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.

Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N*.

Cancer Sci 100   2060-2068 2009.11

Research paper (scientific journal), Joint Work, Accepted

Environmental contamination due to preparation of cyclophosphamide and exposure of pharmacists to it.

Hama T*, Aoyama T, Shirai T, Higuchi S, Yokokawa T, Sugimoto Y.

Jpn J Pharm Health Care Sci 35(10)   693-700 2009.09

Research paper (scientific journal), Joint Work, Accepted

Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib.

Noguchi K, Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y*.

Cancer Science 100   1701-1707 2009.09

Research paper (scientific journal), Joint Work, Accepted

Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide.

Mashima T, Sato S, Okabe S, Miyata S, Matsuura M, Sugimoto Y, Tsuruo T, Seimiya H*.

Cancer Sci 100   1556-1562 2009.08

Research paper (scientific journal), Joint Work, Accepted

CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells.

Takeshita A*, Yamakage N, Shinjo K, Ono T, Hirano I, Nakamura S, Shigeno K, Tobita T, Maekawa M, Kiyoi H, Naoe T, Ohnishi K, Sugimoto Y, Ohno R.

Leukemia 23   1329-136 2009.07

Research paper (scientific journal), Joint Work, Accepted

CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukemia and lymphoma.

Takeshita A*, Shinjo K, Yamakage N, Ono T, Hirano I, Matsui H, Shigeno K, Nakamura S, Tobita T, Maekawa M, Ohnishi K, Sugimoto Y, Kiyoi H, Naoe T, Ohno R.

Br J Haematol 146   34-43 2009.06

Research paper (scientific journal), Joint Work, Accepted

Pharmacological interplay between breast cancer resistance protein and gefitinib in epidermal growth factor receptor signaling.

Katayama K, Shibata K, Mitsuhashi J, Noguchi K, Sugimoto Y.

Anticancer Reserch 29 ( 4 ) 1059-1065 2009.04

Research paper (scientific journal), Joint Work, Accepted

Identification of cytochrome P450s required for fumitoremorgin biosynthesis in Aspergillus fumigatus.

Kato, N, Suzuki H, Takagi H, Asami Y, Kakeya H, Uramoto M, Usui T, Takahashi S, Sugimoto Y, Osada H*.

Chembiochem 10   920-928 2009.03

Research paper (scientific journal), Joint Work, Accepted

Identification of cytochrome P450s required for fumitremorgin biosynthesis in Aspergillus fumigatus.

Kato, N, Suzuki H, Takagi H, Asami Y, Kakeya H, Uramoto M, Usui T, Takahashi S, Sugimoto Y, Osada H.

Chembiochem: a European journal of chemical biology 10 ( 5 ) 920-928 2009.03

Research paper (scientific journal), Single Work, Accepted

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions.

'Mashima T, Sato S, Sugimoto Y, Tsuruo T, Seimiya, H*.'

Oncogene 28 ( 1 ) 9-19 2009.01

Research paper (scientific journal), Joint Work, Accepted

Functions of breast cancer resistance protein (BCRP/ABCG2) in chemotherapy.

'Noguchi K, Katayama K, Mitsuhashi J, Sugimoto Y*.'

Advanced Drug Delivery Reviews (/Elsevier)  61   26-33 2009.01

Research paper (scientific journal), Joint Work, Accepted

Pharmacological Interplay between breast cancer resistance protein and gefitinib in epidermal growth factor receptor signaling.

Katayama K, Shibata K, Mitsuhashi J, Noguchi K, Sugimoto Y*.

Anticancer Research 29   1059-1065 2009.01

Research paper (scientific journal), Joint Work, Accepted

CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukemia and lymphoma.

Takeshita A, Shinjo K, Yamakage N, Ono T, Hirano I, Matsui H, Shigeno K, Nakamura S, Tobita T, Maekawa M, Ohnishi K, Sugimoto Y, Kiyoi H, Naoe T, Ohno R.

British journal of haematology 146   34-43 2009

Research paper (scientific journal), Joint Work, Accepted

CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells.

Takeshita A, Yamakage N, Shinjo K, Ono T, Hirano I, Nakamura S, Shigeno K, Tobita T, Maekawa M, Kiyoi H, Naoe T, Ohnishi K, Sugimoto Y, Ohno R.

Leukemia  2009

Research paper (scientific journal), Single Work, Accepted

Acyl-CoA synthetase as a cancer survival factor: its inhibition enhances the efficacy of etoposide.

Mashima T, Sato S, Okabe S, Miyata S, Matsuura M, Sugimoto Y, Tsuruo T, Seimiya H.

Cancer Science  2009

Research paper (scientific journal), Joint Work, Accepted

Breast cancer resistance protein (BCRP) is a molecular determinant of the outcome of photodynamic therapy (PDT) for centrally located early lung cancer.

Usuda J, Tsunoda Y, Ichinose S, Ishizumi T, Ohtani K, Maehara S, Ono S, Tsutsui H, Ohira T, Okunaka T, Furukawa K, Sugimoto Y, Kato H, Ikeda N.

Lung Cancer  2009

Research paper (scientific journal), Joint Work, Accepted

Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib.

Noguchi K., Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y.

Cancer Science  2009

Research paper (scientific journal), Joint Work, Accepted

標的タンパク質・標的酵素の遺伝子多型と薬剤感受性.

杉本芳一.

腫瘍内科 (/科学評論社)  2(2)   136-144 2008.04

Research paper (scientific journal), Single Work, Accepted

非小細胞肺癌患者における免疫染色法を用いたBreast Cancer-Resistance Proteinの発現とGefitinibの治療効果.

'及川武史, 大平達夫, 臼田実男, 菅泰博, 中嶋英治, 西條天基, 坪井正博, 平野隆, 杉本芳一, 加藤治文*.'

東京医科大学雑誌 66(2)   66(2) 2008.04

Research paper (conference, symposium, etc.), Joint Work, Accepted

FOXO transcription factor-dependent p15INK4b and p19INK4d expression.

'Katayama K, Nakamura A, Sugimoto Y, Tsuruo T, Fujita N*.'

Oncogene 27 ( 12 ) 1677-1686 2008.03

Research paper (scientific journal), Joint Work, Accepted

癌化学療法におけるABCタンパク質-ABCB1とABCG2-.

杉本芳一.

最新医学 (/最新医学社)  62(11)   2528-2533 2007.11

Research paper (scientific journal), Single Work, Accepted

Breast cancer resistance protein (BCRP) affected acquired resistance to gefitinib in a “never-smoked female patient with advanced non-small cell lung cancer."

Usuda J, Ohira T, Suga Y, Oikawa Ichinose S, Maehara S, Ohtani K, Kajiwara N, Tsutsui H, Tsuboi M, Hirano Furukawa K, Okunaka T, Sugimoto Y, Kato H*.

Lung Cancer 58(2)   296-299 2007.11

Research paper (conference, symposium, etc.), Joint Work, Accepted

Flavonoids inhibit breast cancer resistance protein-mediated drug resistance: transporter specificity and structure-activity relationship.

'Katayama K, Masuyama K, Yoshioka S, Hasegawa H, Mitsuhashi J, Sugimoto Y*.'

Cancer Chemotherpy and Pharmacology 60(6)   789-797 2007.11

Research paper (scientific journal), Joint Work, Accepted

Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer.

'Mitsuhashi J, Tsukahara S, Suzuki R, Oh-hara Y, Nishi S, Hosoyama H, Katayama K, Noguchi K, Minowa S, Shibata H, Ito Y, Hatake K, Aiba K, Takahashi S, Sugimoto Y*.'

Human Gene Therapy 18 ( 10 ) 895-906 2007.10

Research paper (scientific journal), Joint Work, Accepted

Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients.

'Takahashi S, Aiba K, Ito Y, Hatake K, Nakane M, Kobayashi T, Minowa S, Shibata H, Mitsuhashi J, Tsukahara S, Ishikawa E, Suzuki R, Tsuruo T, Sugimoto Y*.'

Cancer Science 98(10)   1609-1616 2007.10

Research paper (scientific journal), Joint Work, Accepted

Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein.

'Katayama K, Yoshioka S, Tsukahara S, Mitsuhashi J, Sugimoto Y*.'

Molecular Cancer Therapeutics 6   2092-2102 2007.07

Research paper (scientific journal), Joint Work, Accepted

The identification of two germ-line mutations in the human breast cancer resistance protein gene that result in the expression of a low/non-functional protein.

'Yoshioka S, Katayama K, Okawa C, Takahashi S, Tsukahara S, Mitsuhashi J, Sugimoto Y*.'

Pharmaceutical Research 24   1108-1117 2007.06

Research paper (scientific journal), Joint Work, Accepted

新しい戦略による抗がん剤のスクリーニングのための委員会報告 ー制がん候補物質のスクリーニング成績・第11報ー.

'矢守隆夫*, 安藤俊夫, 上原至雅, 小野眞弓, 河野通明, 済木育夫, 内藤幹彦, 早川洋一, 鶴尾隆, 吉田稔, 杉本芳一, 馬島哲夫.'

癌と化学療法 34　supplement I   34 supplement I 2007.03

Research paper (scientific journal), Joint Work, Accepted

Estrogen-mediated posttranscriptional downregulation of P-glycoprotein in MDR1-transduced human breast cancer cells.

'Mutoh K, Tsukahara S, Mitsuhashi J, Katayama K, Sugimoto Y*.'

Cancer Science 97   1198-1204 2006.11

Research paper (scientific journal), Joint Work, Accepted

A T3587G Germline Mutation of the MDR1 Gene Encodes a Non-functional P-glycoprotein.

'Mutoh K, Mitsuhashi J, Kimura Y, Tsukahara S, Ishikawa E, Sai K, Ozawa S, Sawada J, Ueda K, Katayama K, Sugimoto Y*.'

Molecular Cancer Therapeutics 5   877-884 2006.04

Research paper (scientific journal), Joint Work, Accepted

薬学生の病院研修・臨床研究・症例検討における個人情報保護法への対応.

杉本芳一.

日本医療薬学会会報 (/日本医療薬学会)  10   16-21 2006.03

Research paper (scientific journal), Single Work, Accepted

Functional SNPs of BCRP in drug effect and inhibitor development.

'Yanase K, Tsukahara S, Mitsuhash J, Sugimoto Y*.'

Cancer Letters (/Elsevier)  234   73-80 2006.03

Research paper (scientific journal), Joint Work, Accepted

Modification of pyrimidine derivatives from antiviral agents to antitumor agents.

'Kimura H, Katoh T, Kajimoto T, Node M*, Hisaki M, Sugimoto Y, Majima T, Uehara Y, Yamori T.'

Anticancer Research 26   91-97 2006.02

Research paper (scientific journal), Joint Work, Accepted

Role of Cys-603 in dimer/oligomer formation of the breast cancer resistance protein (BCRP/ABCG2).

'Kage K, Fujita T, Sugimoto Y*.'

Cancer Science 96   866-872 2005.12

Research paper (scientific journal), Joint Work, Accepted

P53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target.

'Mashima T, Oh-hara T, Sato S, Mochizuki M, Sugimoto Y, Yamazaki K, Hamada J, Tada M, Moriuchi T, Ishikawa Y, Kato Y, Tomoda H, Yamori T, Tsuruo T*.'

Journal of the National Cancer Institute 97   765-777 2005.05

Research paper (scientific journal), Joint Work, Accepted

Estrogen-mediated post-transcriptional down-regulation of breast cancer resistance protein/ABCG2.

'Imai Y, Ishikawa E, Asada S, Sugimoto Y*.'

Cancer Research 65   596-604 2005.01

Research paper (scientific journal), Joint Work, Accepted

Antimitotic activity and reversal of breast cancer resistance protein-mediated drug resistance by stilbenoids from Bletilla striata.

'Morita H, Koyama K, Sugimoto Y, Kobayashi J*.'

Bioorganic & Medicinal Chemistry Letters 15   1051-1054 2005.01

Research paper (scientific journal), Joint Work, Accepted

Gefitinib reverses breast cancer resistance protein-mediated drug resistance.

'Yanase K, Tsukahara S, Asada S, Ishikawa E, Imai Y, Sugimoto Y*.'

Molecular Cancer Therapeutics 3   1119-1125 2004.09

Research paper (scientific journal), Single Work, Accepted

Induction of cellular resistance to nucleoside reverse transcriptase inhibitors by the wild-type breast cancer resistance protein.

'Wang X, Nitanda T, Shi M, Okamoto M, Furukawa T, Sugimoto Y, Akiyama S, Baba M*.'

Biochemical Pharmacology 68   1363-1370 2004.09

Research paper (scientific journal), Joint Work, Accepted

Phytoestrogens/Flavonoids Reverse Breast Cancer Resistance Protein/ABCG2 - Mediated Multidrug Resistance.

'Imai T, Tsukahara S, Asada S, Sugimoto Y*.'

Cancer Research 64   4346-4352 2004.06

Research paper (scientific journal), Joint Work, Accepted