果王素对提高吉西他滨联合顺铂治疗肺腺癌小鼠移植瘤敏感性的影响

Reversing multidrug resistance of lung adenocarcinoma xenografts to gemcitabine in combination with cisplatin in mice by Kiwi essence and its mechanism

目的 :本研究旨在观察果王素对提高吉西他滨(gemcitabine)联合顺铂(cisplatin,DDP)(GP方案)治疗肺腺癌小鼠移植瘤敏感性的影响,并初步探讨其可能的作用机制。方法 :40只接种Lewis肺癌的C57BL/6J小鼠随机分成5组,分别给予相应的药物干预:对照组、高剂量果王素组(180 mg/kg)、GP化疗组[DDP(3mg/kg)+吉西他滨(50 mg/kg)]、低剂量果王素(60 mg/kg)联合GP化疗组和高剂量果王素(180 mg/kg)联合GP化疗组。观察肿瘤的生长情况,并于肿瘤接种20 d后处死各组小鼠。分别采用免疫组织化学及反转录聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)法检测肿瘤组织中P-糖蛋白(P-glycoprotein,P-gp)及葡萄糖调节蛋白78(glucose-regulated proteins 78,GRP78)蛋白和m RNA的表达。结果 :各用药组肿瘤的生长速度均低于对照组,以高剂量果王素联合GP化疗组的抑瘤效果最好。低剂量果王素联合GP化疗组、高剂量果王素组及高剂量果王素联合GP化疗组肿瘤中P-gp和GRP78 m RNA及蛋白的表达水平均较对照组和GP化疗组明显降低,差异有统计学意义(P<0.01);且高剂量果王素组及高剂量果王素联合GP化疗组中P-gp和GRP78 m RNA及蛋白的表达水平均较低剂量果王素联合GP化疗组下调。结论 :果王素能明显增强GP方案疗对肺腺癌的疗效,其作用机制可能与下调P-gp及GRP78的表达有关。

Objective: To investigate the effect of Kiwi essence on sensitivity of lung adenocarcinoma xenografts in mice to gemcitabine in combination with cisplatin(DDP)(GP regimen) in mice, and to explore the possible mechanism. Methods: Forty C57BL/6J mice bearing tumor xenografts of Lewis cells were randomized into 5 groups: control group(not tearted with Kiwi essence), high-dose(180 mg/kg) Kiwi essence group, GP group [DDP(3 mg/kg) + gemcitabine(50 mg/kg)], low-dose(60 mg/kg) Kiwi essence combined with GP group, and high-dose(180 mg/kg) Kiwi essence combined with GP group. The growth of tumor xenografts was observed. The mice were sacrificed 20 d after transplantation. The protein and m RNA expression levels of P-glycoprotein(P-gp) and glucose-regulated protein 78(GRP78) in tumor xenografts were detected by immunohistochemistry and reverse transcription-polymerase chain reaction(RT-PCR). Results: The tumor growth was inhibited in various degrees in each drug intervention group as compared with that of the control group, and this inhibition effect was most significant in highdose(180 mg/kg) Kiwi essence combined with GP group. The m RNA and protein expression levels of P-gp and GRP78 were significantly decreased in low-dose Kiwi essence combined with GP group, high-dose Kiwi essence group, and high-dose Kiwi essence combined with GP group, as compared with those of the control group and GP group(P < 0.01). The expression levels of P-gp and GRP78 proteins and m RNAs were significantly decreased in high-dose Kiwi essence group and high-dose Kiwi essence combined with GP group as compared with that of the low-dose Kiwi essence combined with GP group. Conclusion: Kiwi essence can obviously reverse the multidrug resistance of lung adenocarcinoma to GP chemotherapy in mice. This mechanism may be associated to the down-regulation of P-gp and GRP78.