Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines (X.Za., G.W., Q.Ca., X.Zhe., J.Z., Q.Ch., H.H., F.Z.), and Medical and Chemical Institute (B.W., X.Zhu.), China Pharmaceutical University, Nanjing, China.
Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines (X.Za., G.W., Q.Ca., X.Zhe., J.Z., Q.Ch., H.H., F.Z.), and Medical and Chemical Institute (B.W., X.Zhu.), China Pharmaceutical University, Nanjing, China
Drug Metab Dispos. 2018 May;46(5):542-551. doi: 10.1124/dmd.117.079442. Epub 2018 Mar 9.
Multidrug resistance (MDR) is a common limitation for the clinical use of microtubule-targeting chemotherapeutic agents, and it is the main factor for poor prognoses in cancer therapy. Here, we report on deoxypodophyllotoxin (DPT), a promising microtubule inhibitor in phase 1, as a promising candidate to circumvent this obstacle. DPT remarkably suppressed tumor growth in xenograft mice bearing either paclitaxel (PTX)-sensitive MCF-7/S or acquired resistance MCF-7/Adr (MCF-7/A) cells. Also, DPT exhibited similar accumulation in both tumors, whereas PTX displayed much a lower accumulation in the resistant tumors. In vitro, DPT exhibited a much lower resistance index (0.552) than those of PTX (754.5) or etoposide (38.94) in both MCF-7/S and MCF-7/A cells. Flow cytometry analysis revealed that DPT (5 and 10 nM) caused arrest of the G2/M phase in the two cell lines, whereas PTX (up to 10 nM) had no effect on cell-cycle progression of the MCF-7/A cells. Microtubule dynamics assays revealed that DPT destabilized microtubule assembly in a different mode. Cellular pharmacokinetic assays indicated comparable intracellular and subcellular accumulations of DPT in the two cell lines but a much lower retention of PTX in the MCF-7/A cells. Additionally, transport assays revealed that DPT was not the substrate of P-glycoprotein, breast cancer resistance protein, or MDR-associated protein 2, indicating a lower occurrence rate of MDR. DPT might be a promising microtubule inhibitor for breast cancer therapy, especially for treatment of drug-resistant tumors.
多药耐药（MDR）是临床应用微管靶向化疗药物的常见限制因素，也是癌症治疗预后不良的主要因素。在这里，我们报告了脱氧鬼臼毒素（DPT），一种在 1 期具有前景的微管抑制剂，作为克服这一障碍的有前途的候选药物。DPT 显著抑制了携带紫杉醇（PTX）敏感 MCF-7/S 或获得性耐药 MCF-7/Adr（MCF-7/A）细胞的异种移植小鼠的肿瘤生长。此外，DPT 在两种肿瘤中的积累相似，而 PTX 在耐药肿瘤中的积累要低得多。体外实验表明，DPT 在 MCF-7/S 和 MCF-7/A 细胞中的耐药指数（0.552）远低于 PTX（754.5）或依托泊苷（38.94）。流式细胞术分析显示，DPT（5 和 10 nM）在两种细胞系中引起 G2/M 期停滞，而 PTX（高达 10 nM）对 MCF-7/A 细胞的细胞周期进程没有影响。微管动力学分析表明，DPT 以不同的方式破坏微管组装。细胞药代动力学分析表明，DPT 在两种细胞系中的细胞内和亚细胞内积累相当，但在 MCF-7/A 细胞中的 PTX 保留率要低得多。此外，转运实验表明，DPT 不是 P-糖蛋白、乳腺癌耐药蛋白或多药耐药相关蛋白 2 的底物，表明 MDR 的发生率较低。DPT 可能是一种有前途的用于乳腺癌治疗的微管抑制剂，特别是用于治疗耐药性肿瘤。
