title: Epothilone B induces apoptosis and enhances apoptotic effects of ABT-737 on human cancer cells via PI3K/AKT/mTOR pathway.
abstract: OBJECTIVE
  Epothilone B and its derivatives are tested in multiple clinical trials. Epothilone B induces neurotoxic effect in clinical trials; however, low-dose epothilone B regimen can promote neuroprotection and neurogenesis. Thus, the study of new combination chemotherapy regimen incorporating low-dose epothilone B with other chemotherapeutic agents might help to develop epothilone B-based approaches to cancer treatment and avoid the neurotoxicity of epothilone B.
  
  
  METHODS
  Cell proliferation was assessed by SRB cell viability assay. Apoptosis was analyzed by propidium iodide (PI) staining. Mitochondrial membrane depolarization was evaluated using JC-1 staining. The expression of proteins was detected by western blotting.
  
  
  RESULTS
  In this study, we demonstrated that the combination of ABT-737 and low-dose epothilone B showed synergistic anti-proliferation effects on human cancer cells. In addition, epothilone B + ABT-737 synergy was through mitochondria-mediated apoptosis pathway. Furthermore, combination treatment markedly induced the activation of caspase-3 and the cleavage of PARP. The activation of PI3K/Akt/mTOR pathway is associated with resistance to epothilone B. Our data showed that epothilone B plus ABT-737 resulted in a blockade of the PI3K/AKT/mTOR signaling pathway.
  
  
  CONCLUSIONS
  These data indicate that ABT-737 may be a pertinent sensitizer to epothilone B, and the strategy of combining epothilone B with ABT-737 appears to be an attractive option for overcoming the resistance and neurotoxicity of epothilone B.
authors: Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China.
authors: Yang-Ling
authors: YL
authors: Li
authors: Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
authors: Jiao
authors: J
authors: Sun
authors: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.|College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
authors: Xiu
authors: X
authors: Hu
authors: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China.
authors: Yi-Ni
authors: YN
authors: Pan
authors: Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China.
authors: Wei
authors: W
authors: Yan
authors: Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China.
authors: Qing-Yu
authors: QY
authors: Li
authors: Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China.
authors: Fei
authors: F
authors: Wang
authors: Department of Clinical Pharmacology, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China. lnm1013@163.com.|Hangzhou Translational Medicine Research Center, Hangzhou First People's Hospital, Nanjing Medical University, No. 261 Huansha Road, Hangzhou, 310006, Zhejiang, China. lnm1013@163.com.
authors: Neng-Ming
authors: NM
authors: Lin
authors: School of Medicine, Zhejiang University City College, No. 51 Huzhou Street, Hangzhou, 310015, Zhejiang, China. zhangchong@zucc.edu.cn.
authors: Chong
authors: C
authors: Zhang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D034261:Epothilones / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D034261:Epothilones; D009596:Nitrophenols; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C501332:ABT-737; C546842:MTOR protein, human; C093788:epothilone B
keywords: ABT-737; Apoptosis; Epothilone B; Neurotoxicity; PI3K/Akt/mTOR