title   
  

Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells

Arısan, Elif Damla and Kütük, Özgür and Tezil, Tuğsan and Bodur, Çağrı and Telci, Dilek and Başağa, Hüveyda (2010) Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells. Breast Cancer Research and Treatment, 119 (2). pp. 271-281. ISSN 0167-6806 (Print) 1573-7217 (Online)

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Official URL: http://dx.doi.org/10.1007/s10549-009-0343-z

Abstract

Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs.

Item Type:Article
Additional Information:published online ahead of print.
Uncontrolled Keywords:Bcl-2; HA14-1; MCF-7; MDA-MB-231; Cisplatin; Paclitaxel; Chemoresistance
Subjects:Q Science > Q Science (General)
R Medicine > R Medicine (General)
ID Code:11648
Deposited By:Çağrı Bodur
Deposited On:04 Aug 2009 09:57
Last Modified:21 May 2013 10:33

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