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P-glycoprotein modulates oleanolic acid effects in hepatocytes cancer cells and zebrafish embryos.
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2019-11-05 , DOI: 10.1016/j.cbi.2019.108892
Maya Kayouka 1 , Aline Hamade 2 , Eliane Saliba 3 , Fadia Najjar 2 , David Landy 4 , Hélène Greige-Gerges 1
Affiliation  

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.

中文翻译:

P-糖蛋白调节肝细胞癌细胞和斑马鱼胚胎中的齐墩果酸作用。

齐墩果酸(OA)是一种三萜类化合物,广泛存在于植物中,在许多癌症细胞系中均具有抗肿瘤活性。但是,癌细胞会发展成多药耐药性(mdr),从而阻碍了抗癌药的作用。P-糖蛋白(P-gp)是导致mdr的主要原因。因此,分别评估了在不存在和存在P-gp的情况下,OA对人乳腺癌MDA-MB-231和人肝癌HepG2的细胞毒性作用。OA以剂量依赖的方式降低了MDA-MB-231的生存能力,而在相同浓度范围(1-60μM)下,对HepG2却没有观察到明显的作用。此外,在P-gp抑制剂维拉帕米(20 mg / L)的存在下进行了细胞毒性研究。在不存在和存在维拉帕米的情况下,OA对MDA-MB-231表现出相同的作用。然而,在存在维拉帕米的情况下,对HepG2细胞的细胞毒性大大增强(在60μM下72小时后,细胞活力从63.7%下降至25%)。然后在体内在斑马鱼胚胎上证实了该结果。与对照组相比,维拉帕米预处理组观察到5至15μMOA的死亡率和畸形增加;同样,所有胚胎在20μMOA及以上时死亡。这些结果表明,抑制P-gp可增强OA的化学治疗活性。
更新日期:2019-11-05
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