Papers - Ichikawa, Daiju

Immunomodulatory Effect of Proteasome Inhibitors via the Induction of Immunogenic Cell Death in Myeloma Cells

Matsushita M., Kashiwazaki S., Kamiko S., Kobori M., Osada M., Kunieda H., Hirao M., Ichikawa D., Hattori Y.

Pharmaceuticals 16 ( 10 )  2023.10

Research paper (scientific journal), Joint Work, Accepted

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Several anti-cancer drugs are known to have immunomodulatory effects, including immunogenic cell death (ICD) of cancer cells. ICD is a form of apoptosis which is caused by the release of damage-associated molecular patterns (DAMPs), the uptake of cancer antigens by dendritic cells, and the activation of acquired immunity against cancer cells. ICD was originally reported in solid tumors, and there have been few reports on ICD in multiple myeloma (MM). Here, we showed that proteasome inhibitors, including carfilzomib, induce ICD in myeloma cells via an unfolded protein response pathway distinct from that in solid tumors. Additionally, we demonstrated the potential impact of ICD on the survival of patients with myeloma. ICD induced by proteasome inhibitors is expected to improve the prognosis of MM patients not only by its cytotoxic effects, but also by building strong immune memory response against MM cells in combination with other therapies, such as chimeric antigen receptor—T cell therapy.

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GTN057, a komaroviquinone derivative, induced myeloma cells' death in vivo and inhibited c-MET tyrosine kinase

Mikio Okayama, Kota Fujimori, Mariko Sato, Koichi Samata, Koki Kurita, Hiromu Sugiyama, Yutaka Suto, Genji Iwasaki, Taketo Yamada, Fumiyuki Kiuchi, Daiju Ichikawa, Maiko Matsushita, Maki Hirao, Hisako Kunieda, Kohei Yamazaki, Yutaka Hattori

Cancer Med .  12 ( 8 ) 9749 - 9759 2023.04

Research paper (scientific journal), Joint Work, Accepted

A thermoresponsive cationic block copolymer brush-grafted silica bead interface for temperature-modulated separation of adipose-derived stem cells

Nagase K., Okada A., Matsuda J., Ichikawa D., Hattori Y., Kanazawa H.

Colloids and Surfaces B: Biointerfaces (Colloids and Surfaces B: Biointerfaces)  220 2022.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09277765

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Adipose-derived mesenchymal stem cells (ADSCs) have beneficial effects in cell transplantation therapy; these cells are collected from adipose tissue using low-invasive methods. However, to prepare ADSCs for cell therapy, a cell separation method that neither involves modification of the cell surface nor causes loss of cell activity is needed. Here, we aimed to develop ADSC separation columns using thermoresponsive cationic block copolymer brush-grafted beads as packing materials. The block copolymer brush was formed by a bottom cationic segment, poly(N,N-dimethylaminopropylacrylamide) (PDMAPAAm), and an upper thermoresponsive segment, poly(N-isopropylacrylamide) (PNIPAAm), and was grafted in two atom transfer radical polymerization reactions. The copolymer brush-grafted silica beads were packed into a column. An ADSC suspension was introduced into the columns at 37 °C and adsorbed on the copolymer brush-modified beads through electrostatic and hydrophobic interactions with the PDMAPAAm and PNIPAAm segments, respectively. The adsorbed ADSCs eluted from the column by lowering the temperature to 4 °C. In contrast, most Jurkat and vascular endothelial cells eluted at 37 °C, because of the relatively weaker electrostatic interactions with the block copolymer brush compared to ADSCs. Using the prepared column, a mixture of ADSCs and Jurkat cells was separated by changing the column temperature. The recovered ADSCs exhibited cell activity. The developed cell separation column may be useful for isolating ADSCs without cell surface modification, while maintaining cell activity.

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Integrin β5 and β7 expression in lenalidomide-resistant multiple myeloma cells.

Hattori Y, Futo T, Uozaki R, Ichikawa D, Yamaguchi T, Yamamoto T, Matsushita M, Hirao M.

Int J Hematol.  115 ( 4 ) 605 - 608 2022.04

Research paper (scientific journal), Joint Work, Accepted

PAX5-positive plasma cell leukemia presenting as lymphocytosis

Suzuka Tateno, Maki Hirao, Takahide Kikuchi, Yuiko Tsukada, Hisako Kunieda, Makoto Osada, Kohei Yamazaki, Ryunosuke Denda, Shigemichi Hirose, Maiko Matsushita, Daiju Ichikawa, Yutaka Hattori

Rinsho Ketsueki 63 ( 10 ) 1415 - 1420 2022

Research paper (scientific journal), Joint Work, Accepted

Thermally-modulated cell separation columns using a thermoresponsive block copolymer brush as a packing material for the purification of mesenchymal stem cells

Kenichi Nagase , Goro Edatsune, Yuki Nagata, Junnosuke Matsudo, Daiju Ichikawa, Sota Yamada, Yutaka Hattori, Hideko Kanazawa

Biomater Sci. 9 ( 21 ) 7054 - 7064 2021.10

Research paper (scientific journal), Joint Work, Accepted

Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane

Moriwaki Y., Kubo N., Watanabe M., Asano S., Shinoda T., Sugino T., Ichikawa D., Tsuji S., Kato F., Misawa H.

Scientific Reports (Scientific Reports)  10 ( 1 )  2020.12

Research paper (scientific journal), Accepted

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© 2020, The Author(s). α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and regarded as potential therapeutic targets for neurodegenerative conditions, such as Alzheimer’s disease and schizophrenia. Yet, despite the assumed pathophysiological importance of the α7 nAChR, molecular physiological characterization remains poorly advanced because α7 nAChR cannot be properly folded and sorted to the plasma membranes in most mammalian cell lines, thus preventing the analyses in heterologous expression system. Recently, ER-resident membrane protein NACHO was discovered as a strong chaperone for the functional expression of α7 nAChR in non-permissive cells. Ly6H, a brain-enriched GPI-anchored neurotoxin-like protein, was reported as a novel modulator regulating intracellular trafficking of α7 nAChR. In this study, we established cell lines that stably and robustly express surface α7 nAChR by introducing α7 nAChR, Ric-3, and NACHO cDNA into HEK293 cells (Triple α7 nAChR/RIC-3/NACHO cells; TARO cells), and re-evaluated the function of Ly6H. We report here that Ly6H binds with α7 nAChRs on the cell membrane and modulates the channel activity without affecting intracellular trafficking of α7 nAChR.

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Antibody drug separation using thermoresponsive anionic polymer brush modified beads with optimised electrostatic and hydrophobic interactions

Nagase K., Ishii S., Ikeda K., Yamada S., Ichikawa D., Akimoto A.M., Hattori Y., Kanazawa H.

Scientific Reports (Scientific Reports)  10 ( 1 )  2020.12

Research paper (scientific journal), Accepted

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© 2020, The Author(s). Antibody drugs play an important role in biopharmaceuticals, because of the specificity for target biomolecules and reduction of side effects. Thus, separation and analysis techniques for these antibody drugs have increased in importance. In the present study, we develop functional chromatography matrices for antibody drug separation and analysis. Three types of polymers, poly(N-isopropylacrylamide (NIPAAm)-co-2-acrylamido-2-methylpropanesulfonic acid (AMPS)-co-N-phenyl acrylamide (PhAAm)), P(NIPAAm-co-AMPS-co-n-butyl methacrylate (BMA)), and P(NIPAAm-co-AMPS-co-tert-butylacrylamide (tBAAm)), were modified on silica beads through atom transfer radical polymerisation. Rituximab elution profiles were observed using the prepared beads-packed column. Rituximab adsorption at high temperature and elution at low temperature from the column were observed, as a result of the temperature-modulated electrostatic and hydrophobic interactions. Using the column, rituximab purification from contaminants was performed simply by changing the temperature. Additionally, three types of antibody drugs were separated using the column through temperature-modulated hydrophobic and electrostatic interactions. These results demonstrate that the temperature-responsive column can be applied for the separation and analysis of biopharmaceuticals through a simple control of the column temperature.

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Characteristics of a novel target antigen against myeloma cells for immunotherapy

Matsushita M., Saito S., Yokoe S., Ichikawa D., Hattori Y.

Vaccines (Vaccines)  8 ( 4 ) 1 - 13 2020.12

Research paper (scientific journal), Accepted

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© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Despite the availability of therapeutic treatments, multiple myeloma is an incurable haematological disorder. In this study, we aimed to clarify the role of CXorf48 as a therapeutic target in multiple myeloma. Based on a previously identified HLA-A*24:02-restiricted epitope from this novel cancer/testis antigen, we characterized the activities of cytotoxic T lymphocytes (CTLs) specific to this antigen against myeloma cells and evaluated the effects of demethylating agents in increasing antigen expression and enhancing the cytotoxic activity of CTLs. CXorf48 expression was examined by reverse transcription polymerase chain reaction (RT-PCR) using nine myeloma cell lines. Cell lines with low CXorf48 expression were treated by demethylating agents (DMAs), 5-azacytidine (5-aza), and 5-aza-2'-deoxycytidine (DAC) to evaluate gene expression using quantitative RT-PCR. Furthermore, CXorf48-specific CTLs were induced from peripheral blood mononuclear cells of HLA-A*24:02-positive healthy donors to evaluate antigen recognition using ELISpot and51 Cr cytotoxicity assays. CXorf48 was widely expressed in myeloma cells, and gene expression was significantly increased by DMAs. Furthermore, CXorf48-specific CTLs recognized DMA-treated myeloma cells. These findings suggest that CXorf48 is a useful target for immunotherapy, such as vaccination, in combination with demethylating agents for the treatment of patients with myeloma.

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Temperature-modulated cell-separation column using temperature-responsive cationic copolymer hydrogel-modified silica beads

Nagase K., Inanaga D., Ichikawa D., Mizutani Akimoto A., Hattori Y., Kanazawa H.

Colloids and Surfaces B: Biointerfaces (Colloids and Surfaces B: Biointerfaces)  178   253 - 262 2019.06

Research paper (scientific journal), Accepted,  ISSN  09277765

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© 2019 Elsevier B.V. There is strong demand for cell separation methods that do not decrease cell activity or modify cell surfaces. Here, new temperature-modulated cell-separation columns not requiring cell-surface premodification are described. The columns were packed with temperature-responsive cationic polymer hydrogel-modified silica beads. Poly(N-isopropylacrylamide-co-n-butyl methacrylate-co-N,N-dimethylaminopropyl acrylamide) hydrogels with various cationic moieties were attached to silica-bead surfaces by radical polymerization using N,Nʹ-methylenebisacrylamide as a crosslinking agent. The beads were packed into solid-phase extraction columns, and temperature-dependent cell elution from the columns was found using HL-60 and Jurkat cells. The retention HL-60 and Jurkat cells in columns containing cationic beads at 37 °C was 95.3% to 99.6% and 95.0% to 98.8%, respectively. By contrast, beads without cationic properties exhibited low cell retention (20.6% for HL-60 and 32.5% for Jurkat cells). The cells were mainly retained through both electrostatic and hydrophobic interactions. The retained HL-60 (4.9%) and Jurkat cells (40%) were eluted at 4 °C from the column with a low composition of cationic monomer (DMAPAAm, 1 mol% in copolymer), because the temperature-responsive hydrogels on the beads became hydrophilic, decreasing the hydrophobic interactions between the cells and the beads. A higher number of Jurkat cells than HL-60 cells were eluted because of differences in their electrostatic properties (Jurkat cells: −2.53 mV; HL-60 cells: −20.7 mV). The results indicated that cell retention by the hydrogel-coated beads packed in a solid phase extraction column could be modulated simply by changing the temperature.

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A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells

Ichikawa D., Nakamura M., Murota W., Osawa S., Matsushita M., Yanagawa H., Hattori Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)   2019

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

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© 2019 To date, the prognosis of multiple myeloma (MM) in patients harboring cytogenetic abnormalities (CA) involving t (4; 14) and deletion of chromosome 17 remains poor despite recent advances in drug development that include the use of immunomodulatory drugs (IMiDs) such as lenalidomide for MM. To address this issue, we have developed a novel phenylphthalimide derivative, TC11, that is structurally related to IMiDs. It remains unclear how TC11 induces apoptosis of MM cells with high-risk CA. Here, we show that TC11 does not induce degradation of CRBN's substrates, IKZF1/3 and CK1α, and induces apoptosis of CRBN-silenced MM; this effect was independent of the cereblon (CRBN) pathway, which is involved in the mechanism of action of IMiDs used for the treatment of MM. We also revealed that TC11, in contrast to existing IMiDs, induced degradation of MCL1 and activation of caspase-9. Furthermore, inhibition of CDK1 by CGP74514A prevented TC11-induced MCL1 degradation, caspase-9 activation, and the subsequent apoptotic cell death. We showed that ectopic MCL1 expression rescued apoptosis of MM. These observations suggest that TC11 induces apoptotic death caused by degradation of MCL1 during prolonged mitotic arrest. Therefore, our findings suggest that TC11 is a potential drug candidate for high-risk MM.

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A novel derivative (GTN024) from a natural product, komaroviquinone, induced the apoptosis of high-risk myeloma cells via reactive oxygen production and ER stress.

Okayama M, Kitabatake S, Sato M, Fujimori K, Ichikawa D, Matsushita M, Suto Y, Iwasaki G, Yamada T, Kiuchi F, Hirao M, Kunieda H, Osada M, Okamoto S, Hattori Y

Biochem Biophys Res Commun. 505 ( 3 ) 787 - 793 2018.11

Research paper (scientific journal), Joint Work, Accepted

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Early Generated B-1-Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma-like Neoplasia in Aged Mice.

Hayakawa K, Formica AM, Nakao Y, Ichikawa D, Shinton SA, Brill-Dashoff J, Smith MR, Morse HC 3rd, Hardy RR.

J Immunol. 201 ( 2 ) 804 - 813 2018.07

Research paper (scientific journal), Joint Work, Accepted

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NLR Nod1 signaling promotes survival of BCR-engaged mature B cells through up-regulated Nod1 as a positive outcome.

ICHIKAWA Daiju

J Exp Med.  2017.09

Research paper (scientific journal), Joint Work, Accepted

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A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.

ICHIKAWA Daiju

Biochem Biophys Res Commun.  2017.09

Research paper (scientific journal), Joint Work, Accepted

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Synthesis and biological evaluation of the natural product komaroviquinone and related compounds aiming at a potential therapeutic lead compound for high-risk multiple myeloma.

ICHIKAWA Daiju

Bioorg Med Chem Lett.  2017.08

Research paper (scientific journal), Joint Work, Accepted

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Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression.

Hayakawa K, Formica AM, Brill-Dashoff J, Shinton SA, Ichikawa D, Zhou Y, Morse HC 3rd, Hardy RR.

J Exp Med 213 ( 13 ) 3007 - 3024 2016.12

Research paper (scientific journal), Joint Work, Accepted

Identification of Novel HLA-A*24:02-Restricted Epitope Derived from a Homeobox Protein Expressed in Hematological Malignancies

Matsushita, Maiko, Otsuka, Yohei, Tsutsumida, Naoya, Tanaka, Chiaki, Uchiumi, Akane, Ozawa, Koji, Suzuki, Takuma, Ichikawa, Daiju, Aburatani, Hiroyuki, Okamoto, Shinichiro, Kawakami, Yutaka, Hattori, Yutaka

PLOS ONE 11 ( 1 )  2016.01

Research paper (scientific journal), Joint Work,  ISSN  1932-6203

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B cells generated by B-1 development can progress to chronic lymphocytic leukemia.

ICHIKAWA Daiju

Ann N Y Acad Sci.  2015.04

Research paper (scientific journal)

Natural Anti-Intestinal Goblet Cell Autoantibody Production from Marginal Zone B Cells

Ichikawa, Daiju, Asano, Masanao, Shinton, Susan A., Brill-Dashoff, Joni, Formica, Anthony M., Velcich, Anna, Hardy, Richard R., Hayakawa, Kyoko

JOURNAL OF IMMUNOLOGY 194 ( 2 ) 606 - 614 2015.01

Research paper (scientific journal),  ISSN  0022-1767

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