School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
Anticancer Res. 2021 Dec;41(12):6179-6190. doi: 10.21873/anticanres.15437.
BACKGROUND/AIM: We investigated drugs that could sensitize KBV20C cancer cells resistant to eribulin or vincristine (VIC) treatment and assessed their associated mechanisms of action.
Such cancer cells were known to overexpress P-glycoprotein (P-gp). Considering that reserpine (P-gp inhibitor) plays a regulatory role in patients with high blood pressure, we investigated the effect of low doses of 27 blood pressure-regulating drugs on VIC-resistant KBV20C cells. This was done to identify drugs that could be repurposed for sensitizing antimitotic drug-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, rhodamine uptake tests and western-blot analysis were performed to further investigate the mechanism of action of such drugs.
We found that co-treatment with amiodarone, nicardipine, carvedilol, or vardenafil at low doses could highly sensitize KBV20C cells treated with eribulin or VIC. These drugs reduced cellular viability, increased G arrest and up-regulated apoptosis when co-administered with eribulin or VIC. Considering that they sensitize with either co-treatment of eribulin or VIC, we assumed that they can be combined with other antimitotic drugs to sensitize the resistant cancer cells. Through detailed quantitative analysis, we found that eribulin with amiodarone had a higher sensitization effect than eribulin with nicardipine or eribulin with carvedilol. We found that reserpine had the highest P-gp-inhibitory activity, indicating that eribulin- or VIC-reserpine sensitization involves the P-gp inhibitory effects of reserpine. However, we found that amiodarone, nicardipine, carvedilol and vardenafil had very low P-gp inhibitory activity. Moreover, we found that cells co-treated with VIC-carvedilol down-regulated expression of pERK.
Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repurposed blood pressure-regulating drugs amiodarone, nicardipine, carvedilol or vardenafil. These findings indicate that the repurposed blood pressure-regulating drugs may potentially be used in drug-resistant cancer patients without any toxic effects due to P-gp inhibition.
背景/目的：我们研究了能够增敏对艾立布林或长春新碱（VIC）治疗耐药的 KBV20C 癌细胞的药物，并评估了它们的相关作用机制。
已知此类癌细胞过表达 P 糖蛋白（P-gp）。考虑到利血平（P-gp 抑制剂）在高血压患者中具有调节作用，我们研究了 27 种降压药物的低剂量对 VIC 耐药 KBV20C 细胞的影响。这是为了在相对较低的剂量下识别可重新用于增敏抗有丝分裂药物耐药 KBV20C 细胞的药物。通过荧光激活细胞分选（FACS）、 Annexin V 分析、罗丹明摄取试验和 Western blot 分析进一步研究了这些药物的作用机制。
我们发现，低剂量的胺碘酮、尼卡地平、卡维地洛或伐地那非与艾立布林或 VIC 联合治疗可高度增敏 KBV20C 细胞。这些药物与艾立布林或 VIC 联合使用时，可降低细胞活力、增加 G1 期阻滞并上调细胞凋亡。考虑到它们与艾立布林或 VIC 联合增敏，我们假设它们可以与其他抗有丝分裂药物联合使用，以增敏耐药癌细胞。通过详细的定量分析，我们发现胺碘酮联合艾立布林的增敏效果优于尼卡地平或卡维地洛联合艾立布林。我们发现利血平具有最高的 P-gp 抑制活性，表明艾立布林或 VIC 与利血平联合增敏涉及利血平的 P-gp 抑制作用。然而，我们发现胺碘酮、尼卡地平、卡维地洛和伐地那非具有非常低的 P-gp 抑制活性。此外，我们发现 VIC-卡维地洛共处理的细胞下调了 pERK 的表达。
高度抗有丝分裂药物耐药的 KBV20C 细胞可以通过与重新使用的降压药物胺碘酮、尼卡地平、卡维地洛或伐地那非联合治疗来增敏。这些发现表明，重新使用的降压药物可能由于 P-gp 抑制而不会产生任何毒性作用，从而有可能用于耐药癌症患者。
