Targeting tyrosine kinases for autophagy induction along with cytoprotective effect in hematopoietic progenitor cells

• Project/Area Number: 22591050
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokyo Medical University
• Principal Investigator: MIYAZAWA Keisuke 東京医科大学, 医学部, 教授 (50209897)
• Co-Investigator(Kenkyū-buntansha): YOKOYAMA Tomohisa 東京医科大学, 医学部, 講師 (40408240)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: オートファジー / チロシンキナーゼ / メシル酸イマチニブ / 小胞体ストレス / 白血病 / 慢性骨髄性白血病 / 細胞保護効果 / プロテアソーム / ユビキチン / アポトーシス

Research Abstract

Treatment with imatinib mesylate (IM), which is used for targeting therapy for chronic myelogenous leukemia, exhibited an effect of an increased viable cell number of non-BCR-ABL-expressing cell lines by inhibiting spontaneous apoptosis along with autophagy induction. IM attenuated the cytotoxic effects of cytosine arabinoside,tunicamycin, and bortezomib as well as inhibiting cell death with serum-deprived culturein an autophagy-dependent manner. In contrast to autophagy-dependent cytoprotection in response to IM, combined treatment with autophagy inhibitor such as clarithromycin, and proteasome inhibitor, bortezomib potently enhanced endoplasmic reticulum (ER)-stress mediated apoptosis in breast cancer cells and myeloma cells. These lines of evidence suggest that manipulation of autophagy can induce cytoprotective effect via attenuationof ER-stress loading in various kinds of cells including hematopoietic progenitor cells.

Research Products

• [Journal Article] Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells (2013)
  • Author(s): Moriya S, Che XF, Komatsu S, Abe A,Kawaguchi T, Gotoh A, Inazu M, Tomoda A, Miyazawa K
  • Journal Title: Int J Oncol Volume: 42 Issue: 5 Pages: 1541-1550
  • DOI: 10.3892/ijo.2013.1870
  • Peer Reviewed
• [Journal Article] Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis. (2013)
  • Author(s): Karasawa S, Azuma M, Kasama T, Sakamoto S, Kabe Y, Imai T, Yamaguchi Y, Miyazawa K, Handa H
  • Journal Title: Mol Pharmacol Volume: 83 Issue: 3 Pages: 613-620
  • DOI: 10.1124/mol.112.082602
  • Peer Reviewed
• [Journal Article] (2013)
  • Author(s): Klionsky DJ, Abdalla FC, Abeliovich H, Miyazawa K, et al
  • Journal Title: Autophagy. Volume: 8 Pages: 445-544
  • Peer Reviewed
• [Journal Article] Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells. (2012)
  • Author(s): Komatsu S, Miyazawa K(co-first author), Moriya S, Takase A, Naito M, Inazu M, Kohno N, Itoh M, Tomoda A
  • Journal Title: Int J Oncol Volume: 40 Pages: 1029-1039
  • Peer Reviewed
• [Journal Article] Enhancement of cytotoxic and pro-apoptotic effects of 2-aminophenoxazine-3-one on the rathepatocellular carcinoma cell line dRLh-84, the human hepatocellular carcinoma cell line HepG2, and the rat normal hepatocellular cell line RLN-10 (2012)
  • Author(s): Takemura A, Che XF, Tabuchi T, Moriya S, Miyazawa K, Tomoda A
  • Journal Title: Oncol Rep Volume: 27 Pages: 347-355
  • DOI: 10.3892/or.2011.1531
  • Peer Reviewed
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy. (2012)
  • Author(s): Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Miyazawa K, et al.
  • Journal Title: Autophagy. Volume: 8 Pages: 445-544
  • Peer Reviewed
• [Journal Article] Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmicreticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells. (2012)
  • Author(s): Komatsu S, Miyazawa K, Moriya S, Takase A, Naito M, Inazu M, Kohno N, Itoh M, Tomoda A.
  • Journal Title: Int J Oncol. Volume: 40 Pages: 1029-1039
  • Peer Reviewed
• [Journal Article] オートファジーを考える その基礎研究から臨床応用への展望 (2012)
  • Author(s): 宮澤啓介
  • Journal Title: 東京医科大学雑誌 Volume: 70 Pages: 389-396
  • NAID: 10031143018
• [Journal Article] Clarithromycin enhances bortezomib-induced cytotoxicity via endoplasmic reticulum stress-mediated CHOP (GADD153) induction and autophagy in breast cancer cells (2012)
  • Author(s): Komatsu S, Miyazawa K, Moriya S, Takase A, Naito M, Inazu M, Kohno N, ItohM, Tomoda A
  • Journal Title: Int J Oncol. Volume: 40 Issue: 4 Pages: 1029-1039
  • DOI: 10.3892/ijo.2011.1317
  • Peer Reviewed
• [Journal Article] Selectively induced apoptosis in human neutrophils in thepresence of oxidative phenoxazines, 2-amino-4,4α-dihydryo-4α-7H-phenoxazine-3-one and 2-aminophenoxazine-3-one, preceded by decrease of intracellular pH, depolarization of the mitochond (2011)
  • Author(s): Tabuchi T, Che XF, Hiraishi K, Adachi M, Miyano K, Sumimoto H, Tabuchi T, Miyazawa K, Tomoda A
  • Journal Title: JPharmacol Sci Volume: 117 Pages: 139-48
  • Peer Reviewed
• [Journal Article] The β-carboline alkaloid harmol induces cell death via autophagy but not apoptosis in human non-small cell lung cancer A549 cells. (2011)
  • Author(s): Abe A, Yamada H, Moriya S, Miyazawa K
  • Journal Title: Biol Pharm Bull Volume: 34 Pages: 1264-1272
  • Peer Reviewed
• [Journal Article] Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells (2011)
  • Author(s): Moriya S, Miyazawa K (co-first author), Kawaguchi T, Che XF, Tomoda A
  • Journal Title: Int J Oncol. Volume: 39 Pages: 981-988
  • DOI: 10.3892/ijo.2011.1072
  • Peer Reviewed
• [Journal Article] Chemoprevention of chemically-induced biliary carcinogenesis in hamsters by vitamin K2 (2011)
  • Author(s): Tsuchida A, Itoi T, Kasuya K, Nagakawa Y, Suzuki M, Ikeda T, Suzuki Y, Aoki T, Miyazawa K
  • Journal Title: Hepatogastroenterology Volume: 58 Pages: 290-297
  • Peer Reviewed
• [Journal Article] D,L-Threo-1-phenyl-2-decanoyl- amino-3-morpholino-1-propanol (DL-PDMP) increases endoplasmic reticulum stress, autophagy and apoptosis accompanying ceramide accumulation via ceramide synthase 5 protein expression in A549 cells. (2011)
  • Author(s): Yamane M, Miyazawa K, Moriya S, Abe A, Yamane S
  • Journal Title: Biochimie Volume: 93 Pages: 1446-1459
  • Peer Reviewed
• [Journal Article] Combined treatment with bortezomib plus bafilomycin A1 enhances the cytocidal effect and induces endoplasmic reticulum stress in U266 myeloma cells: crosstalk among proteasome, autophagy-lysosome and ER stress (2011)
  • Author(s): Kawaguchi T, Miyazawa K (co-first author), Moriya S, Ohtomo T, Che XF, Naito M, Itoh M, Tomoda A
  • Journal Title: Int J Oncol. Volume: 38 Issue: 3 Pages: 643-654
  • DOI: 10.3892/ijo.2010.882
  • Peer Reviewed
• [Journal Article] Rapid decrease of intracellular pH associated with inhibition of Na^+/H^+ exchangerprecedes apoptotic events in the MNK45 and MNK74 gastric cancer cell lines treated with 2-aminophenoxazine-3-one. (2011)
  • Author(s): Nagata H, Che XF, Miyazawa K, Tomoda A, Konishi M, Ubukata H, Tabuchi T
  • Journal Title: Oncol Rep Volume: 25 Pages: 341-346
  • Peer Reviewed
• [Journal Article] Phenoxazine derivatives suppress the infections caused by herpes simplex virus type-1 and herpes simplex virus type-2 intravaginally inoculated into mice (2010)
  • Author(s): Hayashi K, Hayashi T, Miyazawa K, Tomoda A
  • Journal Title: J Pharmacol Sci Volume: 114 Pages: 85-91
  • NAID: 10029889902
  • Peer Reviewed
• [Journal Article] Multicenter phase II trial of vitamin K(2) monotherapy and vitamin K2 plus1alpha-hydroxyvitamin D3 combination therapy for low-risk myelodysplasticsyndromes. (2010)
  • Author(s): Akiyama N, Miyazawa K, Kanda Y, Tohyama K, Omine M, Mitani K, Ohyashiki K
  • Journal Title: Leuk Res. Volume: 34 Pages: 1151-1157
  • Peer Reviewed
• [Journal Article] Anticanceractivity of phenoxazines produced by bovine erythrocytes on colon cancer cells (2010)
  • Author(s): Nakachi T, Tabuchi T, Takasaki A, Arai S, Miyazawa K, Tomoda A
  • Journal Title: Oncol Rep Volume: 23 Pages: 1517-1522
  • Peer Reviewed
• [Journal Article] 2-Aminophenoxazine-3-oneinduces cellular apoptosis by causing rapid intracellular acidification andgenerating reactive oxygen species in human lung adenocarcinoma cells (2010)
  • Author(s): Zheng CL, Che XF, Akiyama S, Miyazawa K, Tomoda A
  • Journal Title: Int JOncol. Volume: 36 Pages: 641-650
  • Peer Reviewed
• [Journal Article] Cytoprotective effect of imatinib mesylate in non-BCR-ABL-expressing cells along with autophagosome formation (2010)
  • Author(s): Ohtomo T, Miyazawa K (co-first author), Naito M, Moriya S, Kuroda M, Itoh M, Tomoda A
  • Journal Title: Biochem Biophys Res Commun Volume: 391 Pages: 310-315
  • Peer Reviewed
• [Journal Article] Cytoprotective effect of imatinib mesylate in non-BCR-ABL-expressing cells along with autophagosome formation. (2010)
  • Author(s): Ohtomo T, Miyazawa K, et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: 391 Pages: 310-315
  • Peer Reviewed
• [Journal Article] Multicenter phase II trial of vitamin K2 monotherapy and vitamin K2 plus 1 alpha-hydroxyvitamin D3 combination therapy for low-risk myelodysplastic syndromes. (2010)
  • Author(s): Akiyama N, Miyazawa K, et al.
  • Journal Title: Leuk Res. Volume: 34 Pages: 1151-1157
  • Peer Reviewed
• [Journal Article] 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells. (2010)
  • Author(s): Zheng CL, Che XF, Akiyama S, Miyazawa K, et al.
  • Journal Title: Int J Oncol. Volume: 36 Pages: 641-650
  • Peer Reviewed
• [Journal Article] Combined treatment with SAHA, bortezomib, and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells
  • Author(s): Komatsu S, Moriya S, Che X-F, Yokoyama T, Kohno N, Miyazawa K
  • Journal Title: Biochem Biophys Res Commun. Volume: (in press)
  • Peer Reviewed
• [Presentation] オートファジーを考えるその基礎研究から臨床応用への展望 (2012)
  • Author(s): 宮澤 啓介
  • Organizer: 第169回東京医科大学医学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-06-02
• [Presentation] Combined treatment with clarithromycin and bortezomib enhances cytotoxicity via endplasmic reticulum stress-meidated CHOP induction and autophagy in breast cancer cells (2012)
  • Author(s): Komatsu S, Miyazawa K, Moriya S, Takase A, Naito M, Inazu M, Kohno N, Itoh M, Tomoda A
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Chicago, USA
• [Presentation] Targeting autophagy with clarithromycin and proteasome with bortezomib enhances ER-stress in breast cancer cells. (2012)
  • Author(s): Komatsu S, Moriya S, Kohno N, Tomoda A, Miyazawa K
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Combined treatment with bortezomib plus macrolide antibiotics enhances ER-stress mediated cytotoxicity in myeloma cells (2012)
  • Author(s): Moriya S, Che XF, Komatsu S, Tomoda A, Miyazawa K
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 2-aminophenoxazine-3-one (Phx-3) induces apoptosis via a ROS/JNK-dependent pathway in human glioblastoma cell line LN229 (2012)
  • Author(s): Che XF, Miyazawa K, Moriya S, Zheng C, Abe A, Tomoda A
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Simultaneously targeting autophagy with macrolide and proteasome with bortezomib in myeloma cells (2012)
  • Author(s): Che XF, Komatsu S, Tomoda A, Miyazawa K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Combined treatment with clarithromycin and bortezomib enhances cytotoxicity via endplasmic reticulum stress-meidated CHOP induction and autophagy in breast cancer cells. (2012)
  • Author(s): Komatsu S, Miyazawa K, Moriya S, Takase A, Naito M, Inazu M, Kohno N, Itoh M, Tomoda A.
  • Organizer: AACR Annual Meeting
  • Place of Presentation: Chicago
• [Presentation] Combined treatment with bortezomib plus macrolide antibiotics enhances ER-stress mediated cytotoxicity in myeloma cells. (2012)
  • Author(s): Moriya S, Che XF, Komatsu S, Tomoda A, Miyazawa K.
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Simultaneously targeting autophagy with macrolide and proteasome with bortezomib in myeloma cells. (2012)
  • Author(s): Moriya S, Che XF, Komatsu S, Tomoda A, Miyazawa K.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] ER stress-mediated cell death by bortezomib and autophagy inhibition in myeloma cells (2011)
  • Author(s): Miyazawa K, Kawaguchi T, Moriya S, Che X-F, Tomoda A
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-10-14
• [Presentation] Anti-EGFR antibody conjugated gold liposome for molecular imaging and therapy on NSCLC cells (2011)
  • Author(s): 横山智央, 宮澤啓介, 野村将春, 後藤典子 , 大 屋 敷 一 馬
  • Organizer: 第70回日本癌学会総会
  • Place of Presentation: 名古屋
• [Presentation] Endoplasmic reticulum stress-mediated CHOP (GADD153) induction is involved in the cytotoxicity of 2-amino-phenoxazine-3-one in cancer cells. (2011)
  • Author(s): 森谷昇太, 宮澤啓介,川口寛裕,車暁芳,友 田 〓夫
  • Organizer: 第34回日本分子生物学会総会
  • Place of Presentation: 横浜
• [Presentation] Cytoprotective autophagy induction by imatinib mesylate in non-BCR-ABL expressing cells (2010)
  • Author(s): Miyazawa K, et al.
  • Organizer: 第52回アメリカ血液学会総会
  • Place of Presentation: 米国,フロリダ州,オーランド
  • Year and Date: 2010-12-06
• [Presentation] Combined treatment with bortezomib plus bafilomycin A1 enhances cytocidal effect along with induction of ER-stress in myeloma cells (2010)
  • Author(s): Miyazawa K, Moriya S, Kawaguchi T, Ohtomo T, Che XF, Maito M, Itoh M, Tomoda A
  • Organizer: 第52回アメリカ血液学会総会
  • Place of Presentation: Orlando, USA
• [Presentation] Cytoprotective autophagy induction by imatinib mesylate in non-BCR-ABL expressing cells. (2010)
  • Author(s): M iyazawa K, OhtomoT, Moriya S, Naito M, Kuroda M, Itoh M, Tomoda A
  • Organizer: 第52回アメリカ血液学会総会
  • Place of Presentation: Orlando, USA
• [Presentation] (2010)
  • Author(s): 森谷昇太,宮澤啓介,川口寛裕,大友理,車暁芳,内藤宗和,伊藤正裕,友田〓夫
  • Organizer: 第33回日本分子生物学会・第83回日本生化学会合同大会
  • Place of Presentation: 神戸
• [Remarks]
  • URL: http://www.tokyo-med.ac.jp/