National Center for Drug Research and Evaluation, National Institute of Health, 00161 Rome, Italy.
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
Toxicol Appl Pharmacol. 2022 Jan 1;434:115816. doi: 10.1016/j.taap.2021.115816. Epub 2021 Nov 29.
Most women with ovarian cancer are treated with chemotherapy before or after surgery. Unfortunately, chemotherapy treatment can cause negative side effects and the onset of multidrug resistance (MDR). The aim of this study is to evaluate the chemosensitizing effect of a natural compound, voacamine (VOA), in ovarian (A2780 DX) and colon (LoVo DX) cancer drug-resistant cell lines which overexpress P-glycoprotein (P-gp), in combination with paclitaxel (PTX), or doxorubicin (DOX) or 5-fluorouracil (5-FU). VOA, a bisindole alkaloid extracted from Peschiera fuchsiaefolia, has already been shown to be effective in enhancing the effect of doxorubicin, because it interferes with the P-gp function. Ovarian cancer cytotoxicity test shows that single treatments with VOA, DOX and PTX do not modify cell viability, while pretreatment with VOA, and then PTX or DOX for 72 h, induces a decrease. In colon cancer, since 5-FU is not a-substrate for P-gp, VOA has no sensitizing effect while in VOA + DOX there is a decrease in viability. Annexin V/PI test, cell cycle analysis, activation of cleaved PARP1 confirm that VOA plus PTX induce apoptotic cell death. Confocal microscopy observations show the different localization of NF-kB after treatment with VOA + PTX, confirming the inhibition of nuclear translocation induced by VOA pretreatment. Our data show the specific effect of VOA which only works on drugs known to be substrates of P-gp.
大多数卵巢癌患者在手术前后都接受化疗。不幸的是，化疗会产生负面副作用，并引发多药耐药（MDR）。本研究旨在评估天然化合物 voacamine（VOA）与紫杉醇（PTX）、多柔比星（DOX）或氟尿嘧啶（5-FU）联合使用对过表达 P 糖蛋白（P-gp）的卵巢（A2780 DX）和结肠（LoVo DX）癌细胞耐药株的化疗增敏作用。VOA 是从 Peschiera fuchsiaefolia 中提取的双吲哚生物碱，已被证明能有效增强多柔比星的作用，因为它能干扰 P-gp 的功能。卵巢癌细胞毒性试验表明，单独使用 VOA、DOX 和 PTX 不会改变细胞活力，而用 VOA 预处理 72 小时后，再用 PTX 或 DOX 处理，则会导致细胞活力下降。在结肠癌中，由于 5-FU 不是 P-gp 的 a-底物，所以 VOA 没有增敏作用，而在 VOA+DOX 中，细胞活力下降。Annexin V/PI 试验、细胞周期分析、cleaved PARP1 的激活证实 VOA 加 PTX 诱导细胞凋亡。共聚焦显微镜观察显示，在用 VOA+PTX 处理后 NF-kB 的定位不同，证实了 VOA 预处理诱导的核转位抑制。我们的数据显示了 VOA 的特异性作用，它仅对已知是 P-gp 底物的药物有效。
