Application of molecular-targeted drugs for treatment of chemotherapy-induced peripheral neuropathy

• Project/Area Number: 16K18965
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kindai University
• Principal Investigator: TSUBAKI Masanobu 近畿大学, 薬学部, 准教授 (30434856)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん化学療法 / 末梢神経障害 / 分子標的薬 / 抗がん剤誘発末梢神経障害 / オキサリプラチン / パクリタキセル

Outline of Final Research Achievements

I show that oxaliplatin and paclitaxel induces the neuropathy through the activation of PKC/ERK pathway in lumber spinal cords. In addition, PKC and MEK　inhibitor suppressed the oxaliplatin- and paclitzxel-induced neuropathy via PKC/ERK pathways. These findings suggest that PKC and MEK inhibitors are potentially useful for oxaliplatin- and paclitaxel-induced neuropathy. As well, these results are summarized as section of presented paper.

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及びパクリタキセル誘発末梢神経障害の予防、治療法は確立されていない。また、末梢神経障害発症機序の詳細は不明である。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及びパクリタキセル誘発性末梢神経障害にPKC/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、オキサリプラチン及びパクリタキセル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] Combination therapy with dacarbazine and statins improved the survival rate in mice with metastatic melanoma. (2019)
  • Author(s): Tsubaki M, Takeda T, Obata N, Kawashima K, Tabata M, Imano M, Satou T, Nishida S.
  • Journal Title: J Cell Physiol. Volume: In press Issue: 10 Pages: 1-15
  • DOI: 10.1002/jcp.28430
  • Peer Reviewed
• [Journal Article] Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB. (2019)
  • Author(s): Tsubaki M, Takeda T, Tomonari Y, Koumoto YI, Imano M, Satou T, Nishida S.
  • Journal Title: Lab Invest. Volume: 99 Issue: 1 Pages: 72-84
  • DOI: 10.1038/s41374-018-0114-8
  • Peer Reviewed
• [Journal Article] RANKL-induced c-Src activation contributes to conventional anti-cancer drug resistance and dasatinib overcomes this resistance in RANK-expressing multiple myeloma cells. (2019)
  • Author(s): Mashimo K, Tsubaki M, Takeda T, Asano R, Jinushi M, Imano M, Satou T, Sakaguchi K, Nishida S.
  • Journal Title: Clin Exp Med. Volume: 19 Issue: 1 Pages: 133-141
  • DOI: 10.1007/s10238-018-0531-4
  • Peer Reviewed
• [Journal Article] Tamoxifen suppresses paclitaxel-, vincristine-, and bortezomib-induced neuropathy via inhibition of the protein kinase C/extracellular signal-regulated kinase pathway. (2018)
  • Author(s): Tsubaki M, Takeda T, Matsumoto M, Kato N, Yasuhara S, Koumoto YI, Imano M, Satou T, Nishida S.
  • Journal Title: Tumour Biol. Volume: 40 Issue: 10 Pages: 1-13
  • DOI: 10.1177/1010428318808670
  • Peer Reviewed / Open Access
• [Journal Article] Trametinib suppresses chemotherapy-induced cold and mechanical allodynia via inhibition of extracellular-regulated protein kinase 1/2 activation. (2018)
  • Author(s): Tsubaki M, Takeda T, Matsumoto M, Kato N, Asano RT, Imano M, Satou T, Nishida S.
  • Journal Title: Am J Cancer Res. Volume: 8 Pages: 1239-1248
  • Peer Reviewed / Open Access
• [Journal Article] The MIP-1α autocrine loop contributes to decreased sensitivity to anticancer drugs. (2018)
  • Author(s): Tsubaki M, Takeda T, Tomonari Y, Mashimo K, Koumoto YI, Hoshida S, Itoh T, Imano M, Satou T, Sakaguchi K, Nishida S.
  • Journal Title: J Cell Physiol. Volume: 233 Issue: 5 Pages: 4258-4271
  • DOI: 10.1002/jcp.26245
  • Peer Reviewed
• [Journal Article] Pioglitazone inhibits cancer cell growth through STAT3 inhibition and enhanced AIF expression via a PPARγ-independent pathway. (2018)
  • Author(s): Tsubaki M, Takeda T, Tomonari Y, Kawashima K, Itoh T, Imano M, Satou T, Nishida S.
  • Journal Title: J Cell Physiol. Volume: 233 Issue: 4 Pages: 3638-3647
  • DOI: 10.1002/jcp.26225
  • Peer Reviewed / Open Access
• [Journal Article] Rebamipide suppresses 5-fluorouracil-induced cell death via the activation of Akt/mTOR pathway and regulates the expression of Bcl-2 family proteins. (2018)
  • Author(s): Tsubaki M, Takeda T, Asano RT, Matsuda T, Fujimoto SI, Itoh T, Imano M, Satou T, Nishida S.
  • Journal Title: Toxicol In Vitro. Volume: 46 Pages: 284-293
  • DOI: 10.1016/j.tiv.2017.10.019
  • Peer Reviewed / Open Access
• [Journal Article] Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells. (2017)
  • Author(s): Fujiwara D, Tsubaki M, Takeda T, Tomonari Y, Koumoto YI, Sakaguchi K, Nishida S.
  • Journal Title: Tumour Biol. Volume: 39 Pages: 1-11
  • Peer Reviewed / Open Access
• [Journal Article] Contributions of MET activation to BCR-ABL1 tyrosine kinase inhibitor resistance in chronic myeloid leukemia cells. (2017)
  • Author(s): Tsubaki M, Takeda T, Kino T, Sakai K, Itoh T, Imano M, Nakayama T, Nishio K, Satou T, Nishida S.
  • Journal Title: Oncotarget. Volume: 8 Issue: 24 Pages: 38717-38730
  • DOI: 10.18632/oncotarget.16314
  • Peer Reviewed / Open Access
• [Presentation] PKC阻害剤による抗がん剤誘導末梢神経障害抑制効果 (2018)
  • Author(s): 加藤菜月、椿正寛、武田朋也、川島啓司、地主みなみ、藤本伸一郎、森井悠介、西田升三.
  • Organizer: 第68回日本薬学会近畿支部総会・大会
• [Presentation] オキサリプラチン誘発末梢神経障害はPKC/MEK阻害剤で抑制できる (2016)
  • Author(s): 松本 幹広、椿 正寛、武田 朋也、木野 稔己、友成 佳加、西田 升三.
  • Organizer: 第66回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪薬科大学（大阪府高槻市）
  • Year and Date: 2016-10-15