丹皮酚逆转卵巢癌SKOV3/DDP细胞多药耐药性的机制

The mechanisms of paeonol reversing multidrug resistance in ovarian cancer SKOV3/DDP cells

本文在卵巢癌耐药性SKOV3/DDP细胞中,检测丹皮酚(paeonol,PL)逆转卵巢癌耐药的作用,探讨其逆转耐药的机制。结果显示,PL对SKOV3/DDP细胞具有耐药逆转作用。流式细胞术检测发现,PL可浓度依赖性地抑制P糖蛋白(P-glycoprotein, P-gp)功能;采用荧光定量PCR和细胞免疫荧光技术,检测发现15、30和60μmol·L^(-1)PL对MDR1/P-gp和异黏蛋白(metadherin,MTDH)的抑制作用,及对磷酸酶和张力蛋白类似物(phosphataseandtensinhomolog,PTEN)的诱导作用均逐渐增强(P <0.01,P <0.05)。PI3K抑制剂LY294002对PTEN m RNA的诱导和MTDH m RNA的抑制作用均强于或相当于60μmol·L^(-1) PL组,但其诱导PTEN蛋白和抑制MTDH蛋白的作用仅与15μmol·L^(-1) PL组相当。本研究表明, PL对SKOV3/DDP细胞的逆转耐药作用可能与抑制P-gp功能和MDR1/P-gp、MTDH表达,诱导PTEN表达有关,为PL作为耐药逆转剂应用于卵巢癌耐药治疗提供了理论依据。

The purpose of this research is to investigate the effects and mechanisms of paeonol（PL）, a phenolic compound found in many traditional Chinese formulations, on reversing drug resistance in the ovarian cancer resistant SKOV3/DDP cells. The results showed that PL had significant drug-resistant reversal effect on SKOV3/DDP cells. Flow cytometry showed that PL could inhibit P-glycoprotein（P-gp） function in a concentration-dependent manner. Fluorescent quantitative PCR and cell immunofluorescence techniques were used to detect mechanisms of action. Results revealed that both the inhibitory effect on MDR1/P-gp and metadherin（MTDH） expression and the induction effect on phosphatase and tensin homolog（PTEN）, by 15, 30, and 60 μmol·L^（-1） PL, were increased with increased concentrations of PL（P 〈0.01, P 〈0.05）. The inhibitory effect on MTDH m RNA and the induction effect on PTEN m RNA, by PI3 K inhibitor LY294002, were stronger or equivalent to that of the 60 μmol·L^（-1） PL treated group; however, the inhibition or induction effect on MTDH or PTEN protein were only comparable to the 15 μmol·L^（-1） PL treated group. The present study shows that the effect of PL on SKOV3/DDP cells may be related to the inhibition of P-gp function and expression, the inhibition of MDR1, MTDH expression, and the induction of PTEN expression, all which can provide a theoretical foundation for PL as a drug resistance reversal agent on the treatment of ovarian cancer chemotherapy resistance.