5-aza-2'-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells.

Abstract

Treating lung cancer cell lines using low-dose 5-aza-2'-deoxycytidine (DAC) caused an accumulation of procaspase-9 through mRNA upregulation, but the cells did not undergo apoptosis. However, when cells were treated with DAC and infected with a low dose of a recombinant wild-type p53 adenovirus vector (Ad-p53), a synergistic growth inhibitory effect was observed. Combination treatment induced Apaf-1 and procaspase-9 expression in which cytochrome c releases by Ad-p53 triggered the mitochondrial pathway of apoptosis. Selective blockage of caspase-9 activities by Z-LEHD-FMK completely attenuated DAC-induced enhancement of apoptosis mediated by Ad-p53 infection, and ectopic overexpression of procaspase-9 sensitized cells to Ad-p53-induced apoptosis in p53-null cells. In addition, DAC sensitized lung cancer cells to cisplatin and paclitaxel. Induction of the mitochondrial pathway of apoptosis using a slightly toxic dose of DAC may therefore be a strategy for treating lung cancer, and DAC treatment may have clinical implications when combined with chemotherapy or apoptosis-inducing gene therapy.

• Authors: Yoshihito Gomyo, Ji-ichiro Sasaki, Cynthia Branch, Jack A Roth, Tapas Mukhopadhyay
• Journal: Oncogene (Oncogene) Vol. 23 Issue 40 Pg. 6779-87 (Sep 02 2004) ISSN: 0950-9232 [Print] England
• PMID: 15273730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• Tumor Suppressor Protein p53
• Decitabine
• CASP9 protein, human
• Caspase 9
• Caspases
• Azacitidine

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects, physiology)
• Azacitidine (analogs & derivatives, pharmacology)
• Caspase 9
• Caspases (genetics)
• Cell Line, Tumor
• Decitabine
• Gene Expression Regulation, Enzymologic (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Lung Neoplasms (pathology)
• Tumor Suppressor Protein p53 (physiology)