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http://dx.doi.org/10.5352/JLS.2014.24.10.1137

Endogenous Nitric Oxide Strengthens Doxorubicin-induced Apoptosis in Human Colorectal Cell Lines  

Im, Soon Jae (Toxicology Laboratory, Faculty of Biotechnology, College of Applied Life Science, SARI, Jeju National University)
Kim, Ji Hye (Toxicology Laboratory, Faculty of Biotechnology, College of Applied Life Science, SARI, Jeju National University)
Kim, Min Young (Toxicology Laboratory, Faculty of Biotechnology, College of Applied Life Science, SARI, Jeju National University)
Publication Information
Journal of Life Science / v.24, no.10, 2014 , pp. 1137-1143 More about this Journal
Abstract
Doxorubicin is a general chemotherapy drug widely used for a number of cancers. However, the correlation between endogenous nitric oxide ($NO^{\bullet}$) levels and chemoresistance to doxorubicin remains unclear. In this study, we investigated the effect of endogenous $NO^{\bullet}$ on the anticancer activity of doxorubicin in human colon cancer cell lines HCT116 and HT29 with different p53 status. The cells were treated with either doxorubicin alone or in combination with the $NO^{\bullet}$ synthase (NOS) inhibitor $N^G$-monomethyl-L-arginine (NMA). Doxorubicin differentially inhibited the growth of both the HCT116 (p53-WT) and HT29 (p53-MUT) cells, which was mitigated by cotreatment with NMA. Further studies revealed that inhibition of endogenous $NO^{\bullet}$ mitigated doxorubicin-induced apoptosis in the HCT116 and HT29 cells, as evidenced by apoptotic DNA fragmentation and the sub-G1 peak of apoptotic markers. Apoptosis was delayed in the HT29 cells, and its magnitude was greatly reduced, underscoring the importance of the modulation of p53 in the response. RT-PCR analysis revealed that doxorubicin down-regulated levels of inhibitors of the apoptosis family (cellular IAP-1 and-2). Collectively, these data show that induction of apoptosis by doxorubicin in human colon cancer cells is possibly related to modulation of endogenous $NO^{\bullet}$, the expression of the IAP family of genes, and the status of p53. The underlying mechanisms may represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy for colon cancer.
Keywords
Apoptosis; doxorubicin; endogenous nitric oxide; human colon cancer cells; inhibitors of apoptosis;
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