Vitamin E succinate in combination with mda-7 results in enhanced human ovarian tumor cell killing through modulation of extrinsic and intrinsic apoptotic pathways.
Adenovirus-mediated mda-7 (Ad-mda7) gene transfer has been shown to induce apoptosis in various human cancer cells while sparing normal cells. Vitamin E succinate (VES) is also known to exhibit antitumor activity against a number of human cancer cell lines. We hypothesized that a combination of the two agents would produce an enhanced antitumor effect in MDAH2774 human ovarian cancer cells. Treatment of MDAH2774 cells with Ad-mda7 plus VES resulted in enhanced antitumor activity that involved the activation of two apoptotic pathways. Activation of the extrinsic pathway was demonstrated by increased cell-surface Fas expression and cleavage of Bid and caspase-8. Activation of the intrinsic pathway was demonstrated by disruption of mitochondrial potential; and activation of downstream capase-9 and caspase-3 via cytochrome C release. In contrast, the combination of Ad-mda7 plus VES did not show any antitumor activity against normal fibroblasts, indicating selective tumor cell killing. Our in vitro results provide a basis for further preclinical testing of Ad-mda7 plus VES as a potential cancer treatment strategy.
Shanker
Manish
M
Department of Thoracic and Cardiovascular Surgery/Unit 445, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Gopalan
Began
B
Patel
Suraag
S
Bocangel
Dora
D
Chada
Sunil
S
Ramesh
Rajagopal
R
D000256:Adenoviridae / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004770:Enterovirus / Q000502:physiology; D005260:Female; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D008564:Membrane Potentials; D051336:Mitochondrial Membranes / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology*; D011991:Receptors, Virus / Q000502:physiology*; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099180:Interleukin-24
D007378:Interleukins; D011991:Receptors, Virus; D024505:Tocopherols; D014810:Vitamin E; D000099180:Interleukin-24