Identification of imatinib resistance factor and the therapeutic strategies to overcome resistance in chronic myeloid leukemia

• Project/Area Number: 15K08116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kindai University
• Principal Investigator: NISHIDA Shozo 近畿大学, 薬学部, 教授 (40208187)
• Co-Investigator(Renkei-kenkyūsha): TSUBAKI Masanobu 近畿大学, 薬学部, 准教授 (30434856) ; TAKEDA Tomoya 近畿大学, 薬学部, 助教 (20734031)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 慢性骨髄性白血病 / イマチニブ / BCR-ABL阻害薬 / イマチニブ耐性

Outline of Final Research Achievements

To investigate the underlying mechanisms associated with resistance to imatinib, we established imatinib-resistant chronic myeloid leukemia (CML) cell lines. The resistant cell lines activation of MET. In addition, MET inhibitor reversed the imatinib-resistance of the drug-resistant cell lines. These findings suggest that MET inhibitors are potentially useful as an imatinib-resistance CML agent for the treatment of CML cells.
As well, These results are summarized as section of presented paper.

Research Products

• [Journal Article] Bavachin induces the apoptosis of multiple myeloma cell lines by inhibiting the activation of nuclear factor kappa B and signal transducer and activator of transcription 3. (2018)
  • Author(s): Takeda T, Tsubaki M, Tomonari Y, Kawashima K, Itoh T, Imano M, Satou T, Nishida Ｓ.
  • Journal Title: Biomed Pharmacother. Volume: 100 Pages: 486-494
  • DOI: 10.1016/j.biopha.2018.02.019
  • Peer Reviewed
• [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] 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] 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] 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: 0-11
  • 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
• [Journal Article] The sensitivity of head and neck carcinoma cells to statins is related to the expression of their Ras expression status, and statin-induced apoptosis is mediated via suppression of the Ras/ERK and Ras/mTOR pathways. (2017)
  • Author(s): Tsubaki M, Fujiwara D, Takeda T, Kino T, Tomonari Y, Itoh T, Imano M, Satou T, Sakaguchi K, Nishida S.
  • Journal Title: Clin Exp Pharmacol Physiol. Volume: 44 Issue: 2 Pages: 222-234
  • DOI: 10.1111/1440-1681.12690
  • Peer Reviewed / Acknowledgement Compliant
• [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: In press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mangiferin, a novel nuclear factor kappa B-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model. (2016)
  • Author(s): Takeda T, Tsubaki M, Sakamoto K, Ichimura E, Enomoto A, Suzuki Y, Itoh T, Imano M, Tanabe G, Muraoka O, Matsuda H, Satou T, Nishida S.
  • Journal Title: Toxicol Appl Pharmacol. Volume: 306 Pages: 105-112
  • DOI: 10.1016/j.taap.2016.07.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mangiferin enhances the sensitivity of human multiple myeloma cells to anticancer drugs through suppression of the nuclear factor κB pathway (2016)
  • Author(s): Takeda T, Tsubaki M, Kino T, Kawamura A, Isoyama S, Itoh T, Imano M, Tanabe G, Muraoka O, Satou T, Nishida S
  • Journal Title: Int J Oncol Volume: 48 Issue: 6 Pages: 303-309
  • DOI: 10.3892/ijo.2016.3470
  • Peer Reviewed / Open Access
• [Journal Article] RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines. (2016)
  • Author(s): Tsubaki M, Takeda T, Yoshizumi M, Ueda E, Itoh T, Imano M, Satou T, Nishida S.
  • Journal Title: Tumour Biol. Volume: 37 Issue: 7 Pages: 9099-9110
  • DOI: 10.1007/s13277-015-4761-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mangiferin induces apoptosis in multiple myeloma cell lines by suppressing the activation of nuclear factor kappa B-inducing kinase. (2016)
  • Author(s): Takeda T, Tsubaki M, Kino T, Yamagishi M, Iida M, Itoh T, Imano M, Tanabe G, Muraoka O, Satou T, Nishida S.
  • Journal Title: Chem Biol Interact. Volume: 251 Pages: 26-33
  • DOI: 10.1016/j.cbi.2016.03.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Statins inhibited the MIP-1α expression via inhibition of Ras/ERK and Ras/Akt pathways in myeloma cells. (2016)
  • Author(s): Tsubaki M, Mashimo K, Takeda T, Kino T, Fujita A, Itoh T, Imano M, Sakaguchi K, Satou T, Nishida S.
  • Journal Title: Biomed Pharmacother. Volume: 78 Pages: 23-29
  • DOI: 10.1016/j.biopha.2015.12.017
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Statins improve survival by inhibiting spontaneous metastasis and tumor growth in a mouse melanoma model. (2015)
  • Author(s): Tsubaki M, Takeda T, Kino T, Obata N, Itoh T, Imano M, Mashimo K, Fujiwara D, Sakaguchi K, Satou T, Nishida S.
  • Journal Title: Am J Cancer Res. Volume: 5 Pages: 3186-3197
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells. (2015)
  • Author(s): Tsubaki M, Takeda T, Ogawa N, Sakamoto K, Shimaoka H, Fujita A, Itoh T, Imano M, Ishizaka T, Satou T, Nishida S.
  • Journal Title: Leuk Res. Volume: 39 Issue: 4 Pages: 445-52
  • DOI: 10.1016/j.leukres.2015.01.016
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 新規NF-kappaB/STAT3 阻害剤による多発性骨髄腫でのアポトーシス誘導機構の解析. (2018)
  • Author(s): 小泉 翔太郎, 椿 正寛, 武田 朋也, 浅野 良太, 川島 啓司, 西田 升三.
  • Organizer: 日本薬学会第138回年会
• [Presentation] Statins によるRas/ERK 及びRas/mTOR 経路阻害を介した造血器系腫瘍でのアポトーシス誘導機序. (2017)
  • Author(s): 伊藤 麻祐, 椿 正寛, 武田 朋也, 友成 佳加, 西田 升三.
  • Organizer: 第67回日本薬学会近畿支部総会・大会
• [Presentation] MET/ERK and MET/JNK pathways is involved with imatinibresistance in chronic myeloid leukemia. (2017)
  • Author(s): Masanobu Tsubaki, Tomoya Takeda, Yu-ichi Koumoto, Shin-ichiro Fujimoto, Shozo Nishida.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] PioglitazoneはSTAT3阻害を介してSurvivinの発現低下及びAIFの発現増加によりアポトーシスを誘導する. (2017)
  • Author(s): 浅野 良太, 椿 正寛, 武田 朋也, 友成 佳加, 藤原 大一朗, 阪口 勝彦, 西田 升三.
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] 多発性骨髄腫でのMIP-1alphaオートクラインは抗がん剤の感受性を低下させ抗がん剤耐性に寄与する. (2017)
  • Author(s): 河本 雄一, 椿 正寛, 武田 朋也, 友成 佳加, 浅野 良太, 川島 啓司, 眞下 恵次, 阪口 勝彦, 西田 升三.
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] MET activation is involved with imatinib-resistance in chronic myeloid leukemia. (2016)
  • Author(s): 椿 正寛、武田 朋也、木野 稔己、友成 佳加、藤本 伸一郎、西田 升三.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-07
• [Presentation] 慢性骨髄性白血病におけるイマチニブ耐性にMET活性化が関与する (2016)
  • Author(s): 椿 正寛、武田 朋也、木野 稔己、友成 佳加、眞下 恵次、藤原 大一朗、藤本 伸一郎、阪口 勝彦、山添 譲、西田 升三.
  • Organizer: 第20回日本がん分子標的治療学会
  • Place of Presentation: 別府国際コンベンションセンター（大分県別府市）
  • Year and Date: 2016-05-31