Jiang Chunxue, Lee Su Hyun, Park Jae Hyeon, Lee Jin-Sol, Park Ji Won, Kim Ju Ri, Lee Song Hee, Kim Hyung Sik, Yoon Sungpil
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
Anticancer Res. 2021 Feb;41(2):687-697. doi: 10.21873/anticanres.14820.
BACKGROUND/AIM: We investigated drugs that could sensitize P-glycoprotein (P-gp)-overexpressing drug-resistant cancer cells to vincristine (VIC) or eribulin treatment and assessed their associated mechanisms of action.
We investigated 15 bipolar drugs (quetiapine, risperidone, clozapine, asenapine, iloperidone, paliperidone, ziprasidone, trifluoperazine, loxapine succinate, pilocarpine, valproic acid, carbamazepine, levetiracetam, topiramate, and felbamate) to identify drugs with a sensitizing effect on VIC-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action.
We found that co-treatment with half the tested drugs (quetiapine, iloperidone, trifluoperazine, loxapine, risperidone, ziprasidone, or felbamate) at low doses could highly sensitize VIC-resistant KBV20C cells. With lower amounts of the bipolar drugs or VIC, we found that among the 15 bipolar drugs tested, 2 combinations (VIC-quetiapine and VIC-trifluoperazine) had much higher sensitization effects, suggesting that lower effective doses were sufficient for sensitizing P-gp-overexpressing resistant cells compared to those required with the other drugs. Furthermore, when we compared quetiapine and trifluoperazine to previously known bipolar drugs (fluphenazine, thioridazine, pimozide, or aripiprazole), we found that aripiprazole, administered at lower doses, had a much higher sensitization effect. We also demonstrated that co-treatment with another anti-mitotic drug (eribulin) increased the sensitization of KBV20C cells similar to VIC. We also found that aripiprazole had higher P-gp-inhibitory activity than the other bipolar drugs, indicating that this activity was involved in the higher level of VIC-aripiprazole sensitization.
Co-treatment of anti-mitotic drug-resistant cancer cells with a low dose of aripiprazole had the strongest sensitization effect and is highly dependent on P-gp-inhibitory activity.
背景/目的：我们研究了能够使过表达P-糖蛋白（P-gp）的耐药癌细胞对长春新碱（VIC）或艾日布林治疗敏感的药物，并评估了其相关作用机制。
我们研究了15种双向药物（喹硫平、利培酮、氯氮平、阿塞那平、伊潘立酮、帕利哌酮、齐拉西酮、三氟拉嗪、洛沙平琥珀酸盐、毛果芸香碱、丙戊酸、卡马西平、左乙拉西坦、托吡酯和非氨酯），以确定在相对低剂量下对VIC耐药的KBV20C细胞具有增敏作用的药物。进行了荧光激活细胞分选（FACS）、膜联蛋白V分析和罗丹明摄取试验，以进一步研究其作用机制。
我们发现，低剂量联合使用半数受试药物（喹硫平、伊潘立酮、三氟拉嗪、洛沙平、利培酮、齐拉西酮或非氨酯）可使VIC耐药的KBV20C细胞高度敏感。使用较少量的双向药物或VIC时，我们发现在所测试的15种双向药物中，2种组合（VIC-喹硫平和VIC-三氟拉嗪）具有更高的增敏效果，这表明与其他药物相比，较低的有效剂量就足以使过表达P-gp的耐药细胞敏感。此外，当我们将喹硫平和三氟拉嗪与先前已知的双向药物（氟奋乃静、硫利达嗪、匹莫齐特或阿立哌唑）进行比较时，我们发现较低剂量的阿立哌唑具有更高的增敏效果。我们还证明，与另一种抗有丝分裂药物（艾日布林）联合治疗可使KBV20C细胞的敏感性增加，类似于VIC。我们还发现，阿立哌唑比其他双向药物具有更高的P-gp抑制活性，表明这种活性与VIC-阿立哌唑更高水平的增敏作用有关。
低剂量阿立哌唑与抗有丝分裂耐药癌细胞联合治疗具有最强的增敏作用，且高度依赖于P-gp抑制活性。
