Doxorubicin에 의한 내인성 산화질소가 인간 대장암 세포주에서의 세포사멸에 미치는 효과

Abstract

Doxorubicin is a general chemotherapy drug widely used for a number of cancers. However, the correlation between endogenous nitric oxide (NO•) levels and chemoresistance to Doxorubicin remains unclear. In this study we investigated the effect of endogenous NO• on the anticancer activity of Doxorubicin in human colon cancer cell lines HCT116 and HT29 with different p53 status. Cells were treated with either Doxorubicin alone or in combination with NO• synthase (NOS) inhibitor NG-monomethyl-L-arginine (NMA). We show that Doxorubicin differentially inhibits the growth of both HCT116 (p53-WT) and HT29 (p53-MUT) cells, which was mitigated by cotreatment with NMA. Further studies reveal that inhibition of endogenous NO• mitigates Doxorubicin-induced apoptosis in HCT116 and HT29 cells as evidenced by apoptotic DNA fragmentation and sub-G1 peak of apoptotic markers detection: Apoptosis was delayed and greatly reduced in magnitude in HT29 cells, underscoring the importance of p53 modulation of the response. RT-PCR analysis revealed that Doxorubicin down-regulated levels of inhibitors of 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 with modulation of endogenous NO•, IAP family geneexpression and p53 status. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy for colon cancer.