Investigation of the mechanism of chemotherapy-induced peripheral neuropathy and development of new therapeutic strategy

• Project/Area Number: 20K07168
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kindai University
• Principal Investigator: TSUBAKI Masanobu 近畿大学, 薬学部, 准教授 (30434856)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 抗がん剤誘発末梢神経障害 / 分子標的薬 / がん化学療法 / 末梢神経障害

Outline of Research at the Start

本研究計画では、抗がん剤治療の際の副作用として発現し、抗がん剤治療の中断の原因の一因となる末梢神経障害の治療法の開発を目指す。具体的には、抗がん剤（オキサリプラチン、パクリタキセル及びボルテゾミブ）誘発末梢神経障害発現機序を明らかにするとともに、その発現機構を抑制する分子標的薬を見出すことで、抗がん剤治療の継続、QOL向上につながる研究を行う。

Outline of Final Research Achievements

We investigated the mechanisms of oxaliplatin, paclitaxel, and bortezomib-induced neuropathy, and found that activation of the ERK pathway in the lumbar region is involved. We also found that molecularly targeted drugs inhibition of the MEK/ERK pathway prevented oxaliplatin-, paclitaxel-, and bortezomib-induced neuropathy via inhibition of the ERK pathway. These results may contribute to the treatment of oxaliplatin-, paclitaxel-, and bortezomib-induced neuropathy in clinical practice. The results of this study are summarized in the main publications section.

Academic Significance and Societal Importance of the Research Achievements

現在、臨床においてオキサリプラチン、パクリタキセル及びボルテゾミブ誘発末梢神経障害の予防、治療法は確立されていない。さらに、これら抗がん剤による末梢神経障害は患者のQOLを低下させるだけではなく、投与の継続も不可能となるため患者は著しく不利益をこうむる。本成果においてオキサリプラチン、パクリタキセル及びボルテゾミブ誘発性末梢神経障害にMEK/ERK経路の活性化が関与することを明らかにし、その抑制薬により完全に末梢神経障害を抑制できることを見出した。これらの結果により、オキサリプラチン、パクリタキセル及びボルテゾミブの継続投与が可能となり、患者の予後、QOLの改善に貢献できると考えている。

Research Products

• [Journal Article] Hypoxia-inducible factor 1α inhibitor induces cell death via suppression of BCR-ABL1 and Met expression in BCR-ABL1 tyrosine kinase inhibitor sensitive and resistant chronic myeloid leukemia cells (2023)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Kimura A, Tanaka R, Nagayoshi S, Hoshida T, Tanabe K, Nishida S.
  • Journal Title: BMB Rep. Volume: 56 Issue: 2 Pages: 78-83
  • DOI: 10.5483/bmbrep.2022-0095
  • Peer Reviewed / Open Access
• [Journal Article] Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy (2023)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Kishimoto K, Takefuji H, Taniwaki Y, Ueda M, Hoshida T, Tanabe K, Nishida S.
  • Journal Title: Cancer Cell Int. Volume: 23 Issue: 1 Pages: 1-13
  • DOI: 10.1186/s12935-023-02884-z
  • Peer Reviewed / Open Access
• [Journal Article] Bim downregulation by activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance in multiple myeloma cells (2023)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Kishimoto K, Tanaka R, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Clin Exp Med. Volume: － Issue: 5 Pages: 1-11
  • DOI: 10.1007/s10238-022-00951-9
  • Peer Reviewed
• [Journal Article] Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells (2023)
  • Author(s): Tsubaki M, Takeda T, Koumoto Y, Usami T, Matsuda T, Seki S, Sakai K, Nishio K, Nishida S.
  • Journal Title: Cell Prolif. Volume: － Issue: 6 Pages: 1-9
  • DOI: 10.1111/cpr.13420
  • Peer Reviewed / Open Access
• [Journal Article] Combination treatment with statins and bezafibrate induces myotoxicity via inhibition of geranylgeranyl pyrophosphate biosynthesis and Rho activation in L6 myoblasts and myotube cells (2022)
  • Author(s): Tsubaki M, Takeda T, Mastuda T, Kimura A, Yanae M, Maeda A, Hoshida T, Tanabe K, Nishida S.
  • Journal Title: J Physiol Pharmacol. Volume: 73 Pages: 137-152
  • Peer Reviewed / Open Access
• [Journal Article] Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells (2022)
  • Author(s): Tsurushima K, Tsubaki M, Takeda T, Matsuda T, Kimura A, Takefuji H, Okada A, Sakamoto C, Ishizaka T, Nishida S.
  • Journal Title: Int J Mol Sci. Volume: 23 Issue: 15 Pages: 1-13
  • DOI: 10.3390/ijms23158681
  • Peer Reviewed / Open Access
• [Journal Article] Perifosine enhances the potential antitumor effect of 5-fluorourasil and oxaliplatin in colon cancer cells harboring the PIK3CA mutation (2021)
  • Author(s): Morii Y, Tsubaki M, Takeda T, Otubo R, Seki S, Yamatomo Y, Imano M, Satou T, Shimomura K, Nishida S.
  • Journal Title: Eur J Pharmacol. Volume: 898 Pages: 173957-173957
  • DOI: 10.1016/j.ejphar.2021.173957
  • Peer Reviewed
• [Journal Article] Interleukin 19 suppresses RANKL-induced osteoclastogenesis via the inhibition of NF-κB and p38MAPK activation and c-Fos expression in RAW264.7 cells. (2021)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Yamamoto Y, Higashinaka A, Yamamoto K, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Cytokine Volume: 144 Pages: 155591-155591
  • DOI: 10.1016/j.cyto.2021.155591
  • Peer Reviewed
• [Journal Article] FTI-277 and GGTI-289 induce apoptosis via inhibition of the Ras/ERK and Ras/mTOR pathway in head and neck carcinoma HEp-2 and HSC-3 cells. (2021)
  • Author(s): Tateishi K, Tsubaki M, Takeda T, Yamatomo Y, Imano M, Satou T, Nishida S.
  • Journal Title: J BUON Volume: 26 Pages: 606-612
  • Peer Reviewed
• [Journal Article] Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells (2021)
  • Author(s): Tsubaki M, Genno S, Takeda T, Matsuda T, Kimura N, Yamashita Y, Morii Y, Shimomura K, Nishida S.
  • Journal Title: Biomedicines Volume: 9 Issue: 1 Pages: 35-35
  • DOI: 10.3390/biomedicines9010035
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells (2021)
  • Author(s): Tsubaki M, Takeda T, Matsuda T, Seki S, Tomonari Y, Koizumi S, Nagatakiya M, Katsuyama M, Yamamoto Y, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Biomedicines Volume: 9 Issue: 1 Pages: 33-33
  • DOI: 10.3390/biomedicines9010033
  • Peer Reviewed / Open Access
• [Journal Article] Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice (2021)
  • Author(s): Kato N, Tateishi K, Tsubaki M, Takeda T, Matsumoto M, Tsurushima K, Ishizaka T, Nishida S.
  • Journal Title: Pharmaceuticals (Basel). Volume: 14 Issue: 1 Pages: 30-30
  • DOI: 10.3390/ph14010030
  • Peer Reviewed / Open Access
• [Journal Article] The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells (2020)
  • Author(s): Tsubaki M, Seki S, Takeda T, Chihara A, Arai Y, Morii Y, Imano M, Satou T, Shimomura K, Nishida S.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 21 Pages: 7905-7905
  • DOI: 10.3390/ijms21217905
  • Peer Reviewed / Open Access
• [Presentation] StatinsによるKRAS変異大腸がんでのオキサリプラチン抗腫瘍作用増強効果 (2022)
  • Author(s): 松田 拓弥、椿 正寛、武田 朋也、島田 咲、木口 結貴、鶴島 克将、星田 唯史、西田 升三.
  • Organizer: 第72回日本薬学会近畿支部総会・大会
• [Presentation] Gabapentin and duloxetine suppresses oxaliplatin and paclitaxel induced neuropathy by inhibiting ERK1/2 activation. (2022)
  • Author(s): Shozo Nishida, Masanobu Tsubaki, Tomoya Takeda, Takuya Matsuda, Akihiro Kimura, Honoka Takefuji.
  • Organizer: he 81th Annual Meeting of the Japanese Cancer Association
• [Presentation] Statins enhance the sensitivity to oxaliplatin-induced cytotoxicity in KRAS-mutated colorectal cancer. (2022)
  • Author(s): Takuya Matsuda, Masanobu Tsubaki, Tomoya Takeda, Shozo Nishida.
  • Organizer: The 5rd International Cancer Research Symposium of Training Plan for Oncology Professionals
  • Int'l Joint Research
• [Presentation] Akt 阻害剤は PIK3CA 変異大腸癌においてオキサリプラチン及び 5-フルオロウラシルの感受性を増大させる (2021)
  • Author(s): 森井 悠介、椿 正寛、武田 朋也、松田 拓弥、山本 裕太、岸本 佳奈、西田 升三
  • Organizer: 第25回日本がん分子標的治療学会学術集会
• [Presentation] Akt inhibitor enhances the sensitivity to oxaliplatin and 5-fluorourasil in PIK3CA-mutated colon cancer (2021)
  • Author(s): Shozo Nishida, Masanobu Tsubaki, Tomoya Takeda, TakuyaMatsuda, Yuuta Yamamoto, Kana Kishimoto
  • Organizer: The 80th Annual Meeting of the Japanese Cancer Association
• [Presentation] Perifosine enhances sensitivity of oxaliplatin and 5-fluorourasil in PIK3CA-mutated colorectal cancer. (2020)
  • Author(s): Yuuta Yamamoto, Masanobu Tsubaki, Tomoya Takeda, Shiori Seki, Shozo Nishida.
  • Organizer: The 79th Annual Meeting of the Japanese Cancer Association
• [Presentation] Rhosin suppressed tumor metastasis by inhibition Rho/YAP pathway and expression of RHAMM and CXCR4. (2020)
  • Author(s): Shuji Genno, Masanobu Tsubaki, Tomoya Takeda, Shozo Nishida.
  • Organizer: The 79th Annual Meeting of the Japanese Cancer Association