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Advanced Pharmaceutical Bulletin
ISSN: 2228-5881      eISSN: 2251-7308  
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Article History
Submitted: 30 Jun 2014
Revised: 20 Nov 2014
First published online: 19 Sep 2015

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Adv Pharm Bull. 2015;5(3):351-359 doi: 10.15171/apb.2015.049
PMID:26504757        PMCID:PMC4616902

Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells

Original Research

Simin Sharifi 1,2, Jaleh Barar 1,3, Mohammad Saeid Hejazi 1,4 * , Nasser Samadi 3,4,5 *

1 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
2 Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
3 Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.
4 Faculty of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
5 Department of Biochemistry and Medical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.



Abstract

Purpose: Doxorubicin is administrated as a single agent in first-line therapy of breast cancer to induce apoptosis in tumor cells. Bax, Bcl-xL, Caspase-8 and 9 proteins are involved in induction of apoptosis. The present study describes Bax, Bcl-xL gene expression and Caspase-8 and 9 protein levels in MCF-7 cells incubated with doxorubicin at different doses an incubation times.

Methods: The cytotoxic effects of doxorubicin were studied using MTT assay. MCF-7 cells were treated with three concentrations of doxorubicin (0.1, 0.5, 1 μM) and incubated for 24, 48 and 72 hours then expression levels of Bax and Bcl-xL genes were elucidated by Real-time RT-PCR technique and protein levels of caspase-8 and caspase-9 proteins were measured using ELISA method. Morphological modifications of the cells were also monitored via light microscopic images.

Results: Doxorubicin decreased the anti-apoptotic Bcl-xL and increased pro-apoptotic Bax mRNA levels. Doxorubicin induced a significant increase in Bax /Bcl-xL ratio in all doses and incubation times (p<0.05). Highest (more than 10 fold) increase in Bax /Bcl-xL ratio was revealed after 48 h incubation of the cells with in all doses of doxorubicin. Doxorubicin also increased caspase-9 level in a time and dose-dependent manner, while caspase-8 level didn't follow time and dose dependency pattern.

Conclusion: Our results confirm that doxorubicin induces mitochondrial-dependent apoptosis by down-regulation of Bcl-xL and up- regulation of Bax and caspase-9 expressions.







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