Abstract
Paclitaxel is a first-line treatment for triple-negative breast cancer (TNBC), but its efficacy is commonly limited by tumor-cell resistance. Vinpocetine is a well-tolerated dietary supplement with pleiotropic cellular effects, including potential anti-tumor activity. In this study, we tested whether and how vinpocetine might enhance the sensitivity of TNBC cells to paclitaxel. A paclitaxel-resistant TNBC cell line (T50RN) was established by incubating MDA-MB-231 cells with escalating concentrations of paclitaxel (0.5-50 nM). The effects of vinpocetine on T50RN cell sensitivity to paclitaxel were examined. T50RN cells were significantly more resistant to paclitaxel than the parental MDA-MB-231 cells. Vinpocetine itself was slightly cytotoxic to cells but considerably enhanced paclitaxel sensitivity in T50RN cells. Expression of PDE1C, a target of vinpocetine, was elevated in T50RN cells. Depletion of PDE1C moderately enhanced paclitaxel sensitivity of T50RN cells, suggesting that PDE1C overexpression might contribute to paclitaxel resistance. In addition, vinpocetine induced microtubule stabilization and significantly enhanced paclitaxel-induced microtubule stabilization. However, vinpocetine could still enhance paclitaxel sensitivity in PDE1C-depleted T50RN cells, indicating that vinpocetine also acts through factor(s) other than PDE1C. P-gp expression and activity were elevated in T50RN cells, and inhibition of P-gp sensitized T50RN cells to paclitaxel. Vinpocetine functionally disrupted P-gp in T50RN cells and further enhanced the death of P-gp-inhibited paclitaxel-treated T50RN cells. Thus, our results revealed that vinpocetine may act on P-gp and PDE1C to facilitate paclitaxel accumulation and paclitaxel-induced stabilization of microtubules in T50RN cells, thereby enhancing the antimitotic effects of paclitaxel and disrupting paclitaxel-resistance mechanisms.