Effect of trastuzumab/AT-101 combination on apoptosis and cytotoxicity in HER2-positive breast cancer cells: A novel combination to effect resistance to anti-HER2 therapy through inhibition of PI3K signaling.
Bildiriler > Özet Bildiri
Yazarlar: Burcak Karaca, Emir Bozkurt, Harika Atmaca, Zeki Surmeli, Atike Pinar, Ulus Ali ŞANLI, Ruchan Uslu
Journal of Clinical Oncology, , , Uluslararası, Özet Bildiri, cilt 32, ss e13512-e13512
DOI: 10.1200/jco.2014.32.15_suppl.e13512
Özet
e13512 Background: Trastuzumab is a humanized monoclonal antibody approved for the treatment of breast cancer with HER2 amplification and/or overexpression. AT-101, the (-/-) enantiomer of gossypol, is a natural polyphenolic compound extracted from the cotton plant with potent cytotoxic effects on various tumor types. In the present study, we have investigated the possible synergistic cytotoxic and apoptotic effects of AT-101 in combination with Trastuzumab in HER2-positive human breast cancer cell lines, MDA-MB-453 and SKBR3. We have further investigated the effect of the combination treatment on the PI3K signaling pathway to elucidate the molecular targets of the combination treatment Methods: Cytotoxicity was assessed by XTT cell viability assay. Apoptosis was shown by using Cell Death Detection ELISA Plus Kit and verified by measuring caspase 3/7 enzyme activity. In order to investigate the molecular mechanism of combination treatment-induced apoptotic activity, cells were pretreated with PI3K inhibitor (LY294002) before Trastuzumab/AT-101 combination treatment, and then DNA fragmentation analysis was done. Results: Combination of Trastuzumab with AT-101 showed strong synergistic cytotoxicity in both breast cancer cells at 72 h, as compared with any agent alone. Combined treatment also induced DNA fragmentation and caspase 3/7 activation in breast cancer cells. PI3K inhibitor LY294002 inhibited the apoptotic effect of combination treatment in both breast cancer cell lines indicating that this combination inhibits the PI3K signaling pathway leading to apoptotic cell death. Conclusions: PI3K pathway is mostly found in Her-2resistance; thus this novel combination of Trastuzumab and AT-101 might be promising for overcoming anti-Her-2 resistance.