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Effect of baicalein on the inhibitory role of cisplatin on the proliferation of ovarian cancer A2780 cells
Zheng Ningze,Tao Liang,Wang Qin
JOURNAL OF NEW MEDICINE ›› 2020, Vol. 51 ›› Issue (5) : 348-353.
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Effect of baicalein on the inhibitory role of cisplatin on the proliferation of ovarian cancer A2780 cells
Objective To evaluate the effect and mechanism of baicalein on the inhibitory role of cicplatin on the proliferation of ovarian cancer A2780 cells.Methods The A2780 cells in the logarithmic growth phase were selected. The cytotoxicity of baicalein on the ovarian cancer A2780 cells was assessed by CCK-8 assay. The difference of IC50 of cisplatin in the A2780 cells treated with and without baicalein was statistically compared. After the treatment with cell gap junction （GJ） pathway inhibitor 18-α-glycyrrhetinic acid （18-α-GA）, the effect of cisplatin on the inhibitory rate of A2780 cells was evaluated. The effect of baicalein treatment on the inhibitory role of cisplatin was assessed. The impact of baicalein on the function of GJ signaling pathway in the A2780 cells was evaluated by Parachute assay. Based on the GEO dataset, the expression levels of GJA1 （Cx43） genes between the normal ovarian epithelial and ovarian cancer epithelial tissues were statistically compared. The effect of baicalein on the expression of Cx43 protein in the A2780 cells was assessed by Western blot. The targeted protein of baicalein was predicted by Swiss Target Prediction database. The interaction network between the targeted proteins and GJ pathway was constructed.Results Baicalein treatment at a dose of≤10 μmol/L provoked no obvious toxicity to the A2780 cells. Compared with cisplatin alone, baicalein treatment at a dose of 10 μmol/L could significantly increase the inhibitory rate of cisplatin on the A2780 cells （P < 0.01）. Administration of 18-α-GA could considerably lower the inhibitory rate of cisplatin on the A2780 cells and significantly reverse the sensitization effect of baicalein on cisplatin （both P < 0.01）. GEO dataset revealed that the expression level of Cx43 mRNA in the ovarian cancer epithelial tissues was significantly lower compared with that in the normal ovarian epithelial tissues （P < 0.05）. Treatment with baicalein could significantly up-regulate the expression level of Cx43 protein （P < 0.01）. Swiss Target Prediction database demonstrated that baicalein directly targeted to the four proteins in the GJ pathway.Conclusion Baicalein can increase the cytotoxicity of cisplatin upon the ovarian cancer A2780 cells, probably correlated with the enhancement of the function of GJ pathway in the A2780 cells.
Baicalein / Ovarian cancer / Cisplatin / Gap junction {{custom_keyword}} /
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Drug resistance limits the clinical application of cisplatin, a widely used chemotherapeutic agent. Gap junction (GJ) is a channel that enhances cytotoxicity of certain chemotherapeutic agents. Baicalein is well known for its antitumor activity. This study investigated the effect of baicalein on cisplatin cytotoxicity and the relationship between this effect and the modulation of the GJ function in connexin 26 (Cx26)-transfected HeLa cells. The sulforhodamine B (SRB) assay was used to examine the effect of baicalein on cell viability. A 'parachute' assay was used to investigate the effect of baicalein on GJ function. The effects of baicalein on cisplatin cytotoxicity and GJ function were assayed by standard colony-forming assays. The expression of Cx26 was monitored by western blotting. It was observed that exposure of Cx26-transfected cells to cisplatin reduced the number of colonies formed in low-density cultures (no GJ formation) and in high-density cultures (GJ formation), but the toxic effect was greater when cells were seeded at a high density. In the absence of connexin expression or with blockage of connexin channels however, cell density had no effect on cisplatin toxicity. Baicalein significantly enhanced cisplatin cytotoxicity, but this effect required the presence of functional GJs between the cells. In conclusion, the dependence of cisplatin toxicity on cell density is mediated by GJs. Baicalein increases cisplatin cytotoxicity through enhancing GJ intercellular communication.
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图1 不同浓度黄芩素作用下卵巢癌A2780细胞的生存率比较图2 黄芩素增加卵巢癌A2780细胞对顺铂的敏感性图3 黄芩素增强A2780细胞的GJ通道功能图4 抑制GJ通道功能可削弱黄芩素的顺铂增敏作用图5 黄芩素的靶蛋白与GJ通道互作网络/
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