Curcumin increases the sensitivity of K562/DOX cells to doxorubicin by targeting S100 calcium-binding protein A8 and P-glycoprotein

摘要

The development of multidrug resistance (MDR) has seriously impeded the efficacy of drug treatment of chronic myeloid leukemia (CML). Recent studies have indicated that S100 calcium-binding protein A8 (S100A8) is associated with the occurrence and development of MDR. Traditional Chinese medicine may provide drugs with the potential to be used as multidrug resistance reversal agents with low toxicity and multi-target characteristics. The present study selected K562/DOX cells, a CML drug-resistant cell line, as a research model, and aimed to examine whether curcumin was able to reverse the resistance to doxorubicin (DOX), and elucidate the underlying molecular mechanisms. An MTT cytotoxicity assay indicated that curcumin at 0.5-2 mu M reversed DOX resistance with a reversal index of 1.3-9.3. Western blot analysis revealed that curcumin treatment caused a downregulation of the expression of P-glycoprotein (P-gp) and S100A8 in a dose- and time-dependent manner. To study the internal association between S100A8 and P-gp, and the S100A8 role in drug resistance reversal, an RNA knockdown assay was conducted; however, S100A8 did not regulate the expression of P-gp or vice versa. After inhibiting the expression of S100A8 with specific small interfering RNA (si-S100A8), the sensitivity K562/DOX cells to DOX was enhanced. In addition, si-S100A8 did not increase the intracellular accumulation of DOX, but increased the intracellular free calcium ion content, and the expression and activity of apoptosis-associated proteins, thereby inducing apoptosis. In conclusion, the present study suggested that inhibition of S100A8 expression increased DOX-induced apoptosis, and curcumin acted independently on S100A8 and P-gp to exert its drug resistance reversal effects