Research on the molecular mechanism of a novel naphthalimide derivative 8c inducing apoptosis in multidrug resistant colon cancer cells / 中国癌症杂志

ABSTRACT

Background and purpose:Suppression of apoptotic signaling pathways is an important factor in tumor cell resistance. Research on cell apoptosis will open up a new way of reversing drug resistance and tumor treatment. This study examined the effects of a novel naphthalimide derivative 8c on multidrug resistant colon cancer HCT116/L-OHP cells and explored the molecular mechanisms underlying the apoptosis induction. Methods: The anti-proliferative effects of 8c were detected by CCK-8 assays and the effects on apoptosis induction were examined by lfow cytometry. The mRNA expression levels of p53, Bax and Bcl-2 were measured by real-time PCR;The protein expressions of p-p53, Bax, Bcl-2 and Cyt-c were detected by Western blot. Results:8c (IC50=8.16 μmol/L) seemed to be more potent than amonaifde (IC50=28.37 μmol/L) against HCT116/L-OHP cells. 8c induced apoptosis on HCT116/L-OHP cell lines through intrinsic or mitochondria dependent pathway. The protein expression of phosphorylation of p53 at Ser-15 was increased, but the mRNA level of p53 did not increase in HCT116/L-OHP cells. Bax protein and mRNA levels were signiifcantly increased, and Bcl-2 protein and mRNA levels were decreased, suggesting an increase of Bax/Bcl-2 ratios. Meanwhile, 8c induced a substantial release of cytochrome c from the mitochondria into the cytosol in HCT116/L-OHP cells. Conclusion: 8c induced cell death signal by inducing the activation p53 phosphorylation which subsequently activated related protein expressions of apoptotic pathway, which may be an important mechanism of 8c on inhibiting proliferation of HCT116/L-OHP resistant cells. All the results suggested that 8c was a potent compound to be developed as an anti-tumor and anti-resistance agent for clinic application in the future.