Bioactive Molecules Research Laboratory, Faculty of Sciences, Section II, Lebanese University, Lebanon.
Laboratoire d'Innovation Thérapeutique, Faculty of Sciences, Section II, Lebanese University, Lebanon.
Chem Biol Interact. 2020 Jan 5;315:108892. doi: 10.1016/j.cbi.2019.108892. Epub 2019 Nov 5.
Oleanolic acid (OA) is a triterpenoid, widely found in plants and possesses antitumor activity in many cancer lines. However, cancer cells develop multidrug resistance (mdr) hindering the effect of anticancer drugs. P-glycoprotein (P-gp) is a major cause of mdr. Therefore, the cytotoxic effect of OA was evaluated on human breast cancer MDA-MB-231 and human liver cancer HepG2 with absence and presence of P-gp, respectively. OA reduced MDA-MB-231 viability in a dose dependent manner, whereas no remarkable effect was observed on HepG2 in the same range of concentrations (1-60 μM). Moreover, cytotoxicity studies were conducted in the presence of verapamil (20 mg/L), a P-gp inhibitor. OA exhibited the same effect on MDA-MB-231 in the absence and presence of verapamil. However, the cytotoxicity was greatly enhanced for HepG2 cells in the presence of verapamil (cell viability dropped from 63.7% to 25% after 72 h at 60 μM). The results were then confirmed in vivo on zebrafish embryos. Increased mortality and malformations were observed in verapamil pretreated group between 5 and 15 μM of OA compared to control; also, all embryos died at 20 μΜ OA and above. These results demonstrate that inhibiting P-gp enhances the chemotherapeutic activity of OA.
齐墩果酸（OA）是一种广泛存在于植物中的三萜类化合物，具有多种抗癌活性。然而，癌细胞会产生多药耐药性（mdr），从而阻碍抗癌药物的效果。P-糖蛋白（P-gp）是 mdr 的主要原因之一。因此，分别在不存在和存在 P-gp 的情况下，评估了 OA 对人乳腺癌 MDA-MB-231 和人肝癌 HepG2 的细胞毒性作用。OA 呈剂量依赖性降低 MDA-MB-231 的活力，而在相同浓度范围内（1-60 μM）对 HepG2 没有明显作用。此外，还在维拉帕米（20 mg/L）存在的情况下进行了细胞毒性研究，维拉帕米是一种 P-gp 抑制剂。OA 在不存在和存在维拉帕米的情况下对 MDA-MB-231 均具有相同的作用。然而，对于 HepG2 细胞，维拉帕米的存在大大增强了其细胞毒性（在 60 μM 时，72 小时后细胞活力从 63.7%降至 25%）。然后在斑马鱼胚胎上进行了体内验证。与对照组相比，在 5 至 15 μM 的 OA 预处理组中，维拉帕米预处理组的死亡率和畸形率增加；此外，所有胚胎在 20 μΜ OA 及以上浓度下均死亡。这些结果表明，抑制 P-gp 可增强 OA 的化疗活性。
