title: P53 dependent and independent apoptosis induced by lidamycin in human colorectal cancer cells.
abstract: Enediyne compound is one class of antibiotics with very potent anti-cancer activity. However, the role of p53 in enediyne antibiotic-induced cell killing remains elusive. Here we reported the involvement of p53 signaling pathway in apoptosis induction by lidamycin (LDM), a member of the enediyne antibiotic family. We found that LDM at low drug concentration of 10 nmol/L induces apoptotic cell death much more effectively in human colorectal cancer cells with wild type p53 than those with mutant or deleted p53. p53 is functionally activated as an early event in response to low dose LDM that precedes the significant apoptosis induction. The primarily activation of mitochondria as well as the activation of p53 transcriptional targets such as Puma, Bad and Bax in HCT116 p53 wild type cells further demonstrates the key role of p53 in mediating the compound-induced apoptosis. This is further supported by the observation that the absence of Bax or Puma decreases apoptosis dramatically while Bcl-2 overexpression confers partially resistance after drug treatment. Activation of p53 signaling pathway leads to activation of caspases and caspases inhibitor VAD-fmk completely blocks low dose LDM induced apoptosis through the inhibition of mitochondria pathway. In contrast, LDM at higher concentration causes rapid apoptosis through more direct DNA damaging mechanism that is independent of activation of p53 and caspases and cannot be blocked by caspase inhibitor. Taken together, LDM induces apoptosis in a p53-dependent manner when given at low doses, but in a p53-independent manner when given at high doses. This dosage-dependent regimen can be applied to cancer clinic based upon the p53 status of cancer patients.
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Chen
authors.forename: Jianming
authors.initials: J
authors.lastname: Jiang
authors.forename: Chunlei
authors.initials: C
authors.lastname: Cheng
authors.forename: Ajing
authors.initials: A
authors.lastname: Yang
authors.forename: Qiyang
authors.initials: Q
authors.lastname: He
authors.forename: Diandong
authors.initials: D
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D053281:Enediynes / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D008564:Membrane Potentials; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D002843:Chromatin; D053281:Enediynes; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C058024:C 1027