期刊
CANCER CELL INTERNATIONAL
卷 14, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1475-2867-14-13
关键词
Apoptosis; NF-kappa B; Caspase activation; Mitochondrial dysfunction; Senescence; MG132; Doxorubicin; Leukemia
类别
资金
- Instituto Mexicano del Seguro Social (IMSS) [FIS/IMSS/PROT/283]
Background: The resistance of cancerous cells to chemotherapy remains the main limitation for cancer treatment at present. Doxorubicin (DOX) is a potent antitumor drug that activates the ubiquitin-proteasome system, but unfortunately it also activates the Nuclear factor kappa B (NF-kappa B) pathway leading to the promotion of tumor cell survival. MG132 is a drug that inhibits I kappa B degradation by the proteasome-avoiding activation of NF-kappa B. In this work, we studied the sensitizing effect of the MG132 proteasome inhibitor on the antitumor activity of DOX. Methods: U937 human leukemia cells were treated with MG132, DOX, or both drugs. We evaluated proliferation, viability, apoptosis, caspase-3, -8, and -9 activity and cleavage, cytochrome c release, mitochondrial membrane potential, the Bcl-2 and Bcl-XL antiapoptotic proteins, senescence, p65 phosphorylation, and pro-and antiapoptotic genes. Results: The greatest apoptosis percentage in U937 cells was obtained with a combination of MG132 + DOX. Likewise, employing both drugs, we observed a decrease in tumor cell proliferation and important caspase-3 activation, as well as mitochondrial membrane potential loss. Therefore, MG132 decreases senescence, p65 phosphorylation, and the DOX-induced Bcl-2 antiapoptotic protein. The MG132 + DOX treatment induced upregulation of proapoptotic genes BAX, DIABLO, NOXA, DR4, and FAS. It also induced downregulation of the antiapoptotic genes BCL-XL and SURVIVIN. Conclusion: MG132 sensitizes U937 leukemia cells to DOX-induced apoptosis, increasing its anti-leukemic effectiveness.
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