SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells.
Limited treatment options are available for chronic myelogenous leukemia (CML) patients who develop imatinib mesylate (IM) resistance. Here we proposed a novel combination regimen, a co-administration of S116836, a novel small molecule multi-targeted tyrosine kinase inhibitor that was synthesized by rational design, and histone deacetylases inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA), to overcome IM resistance in CML. S116836 at low concentrations used in the present study mildly downregulates auto-tyrosine phosphorylation of Bcr-Abl. SAHA, an FDA-approved HDACi drug, at 1 μM has modest anti-tumor activity in treating CML. However, we found a synergistic interaction between SAHA and S116836 in Bcr-Abl-positive CML cells that were sensitive or resistant to IM. Exposure of KBM5 and KBM5-T315I cells to minimal or non-toxic concentrations of SAHA and S116836 synergistically reduced cell viability and induced cell death. Co-treatment with SAHA and S116838 repressed the expressions of anti-apoptosis proteins, such as Mcl-1 and XIAP, but promoted Bim expression and mitochondrial damage. Of importance, treatment with both drugs significantly reduced cell viability of primary human CML cells, as compared with either agent alone. Taken together, our findings suggest that SAHA exerts synergistically with S116836 at a non-toxic concentration to promote apoptosis in the CML, including those resistant to imatinib or dasatinib.
Department of Pathophysiology; Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou, PR China.
Qiangui
Q
Bu
Department of Pathophysiology; Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou, PR China.
Lijing
L
Cui
Department of Hematology; The First Affiliated Hospital; Sun Yat-sen University; Guangzhou, PR China.
Juan
J
Li
Department of Hematology; Guangdong Provincial People's Hospital; Guangzhou, PR China.
Xin
X
Du
Department of Hematology; The First Affiliated Hospital; Sun Yat-sen University; Guangzhou, PR China.
Waiyi
W
Zou
Key Laboratory of Regenerative Biology and Institute of Chemical Biology; Guangzhou Institute of Biomedicine and Health; Chinese Academy of Sciences; Guangzhou, PR China.
Ke
K
Ding
Department of Pathophysiology; Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou, PR China; State Key Laboratory of Ophthalmology; Zhongshan Ophthalmic Center; Sun Yat-sen University; Guangzhou, PR China; Collaborative Innovation Center for Cancer Medicine; State Key Laboratory of Oncology in South China; Sun Yat-Sen University Cancer Center; Guangzhou, PR China.
Jingxuan
J
Pan
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D000077337:Vorinostat
D000970:Antineoplastic Agents; D001549:Benzamides; D006877:Hydroxamic Acids; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000595182:S116836; D014443:Tyrosine; D000077337:Vorinostat; D000068877:Imatinib Mesylate
Bcr-Abl; CML; S116836; T315I mutation; apoptosis; imatinib; resistance; tyrosine kinase inhibitor