BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells

  • Biochem Biophys Rep. 2018 Jul 13;15:69-75. doi: 10.1016/j.bbrep.2018.07.001.
Chisato Inoue  1 ,  Sayaka Sobue  1 ,  Yuka Aoyama  1 ,  Naoki Mizutani  1 ,  Yoshiyuki Kawamoto  1 ,  Yuji Nishizawa  1 ,  Masatoshi Ichihara  1 ,  Akihiro Abe  2 ,  Fumihiko Hayakawa  2 ,  Motoshi Suzuki  3 ,  Yoshinori Nozawa  4 ,  Takashi Murate  1
Affiliations
  • 1. College of Life and Health Sciences, Chubu University, Matsumoto-cho 1200, Kasugai 487-8501, Japan.
  • 2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya 461-8560, Japan.
  • 3. Division of Molecular Oncology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
  • 4. Tokai Gakuin University, Kakamigahara 504-8511, Japan.
PMID: 30073206 DOI: 10.1016/j.bbrep.2018.07.001
Abstract

Imatinib (IMT), a specific tyrosine kinase inhibitor (TKI), has drastically changed the treatment strategy for Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia). However, TKI resistance remains a serious problem for patient prognosis. Here, a Ph+ ALL cell line NphA2 and the IMT-resistant subline NphA2/STIR were analyzed to identify a potential novel treatment strategy. We also examined Other Ph+ ALL cells, MR87 and its IMT-resistant subline, MR87/STIR. IMT induced Apoptosis of NphA2 and MR87 but had no effect on resistant sublines. Increased phosphorylated ERK and BCL2, but not Bcl-xL, were observed in NphA2/STIR compared with NphA2. NphA2/STIR but not NphA2 was moderately sensitive to U0126, an ERK Inhibitor. Interestingly, SP600125, a JNK Inhibitor, was potent in cell growth inhibition and Apoptosis induction of both parental and IMT-resistant NphA2 and MR87 cells. Moreover, NphA2 and MR87 and their IMT-resistant sublines were sensitive to ABT-199, a specific BCL2 inhibitor. The combination of SP600125 and ABT-199 synergistically suppressed both parental and IMT-resistant cells, including one with T315I mutation, suggesting that Ph+ ALL exhibits high sensitivity to ABT-199 and SP600125 regardless of TKI resistance. This combination might be a possible therapeutic strategy for Ph+ ALL in the future.

Keywords
ABL, Abelson kinase; ALL, acute lymphoblastic leukemia; BCL2 inhibitor; BCR, break clustering region; CML, chronic myeloid leukemia; DST, dasatinib; IMT, imatinib; Imatinib-resistance; JNK inhibitor; NRT, nirotinib; Ph+ ALL; Ph+, Philadelphia chromosome positive; Synergistic action; TKI, tyrosine kinase inhibitor.
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