Papers - Sugimoto, Yoshikazu

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

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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.

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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

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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.

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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

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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.

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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

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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.

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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

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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.

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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

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© 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.

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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

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© 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.

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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

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© 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.

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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

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© 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.

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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

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© 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.

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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

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© 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.

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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

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© 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.

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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

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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

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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

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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

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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

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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