Guo Fu-Chun, Wang Li-Qiang, Zhang Jing, Wang Yong-Sheng
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2013 May;44(3):375-8.
To investigate the antitumor effect of the combination of metformin with alpha-cyano-4-hydroxycinnamic acid (CHC, a MCT1 inhibitor) in the treatment of Lewis lung cancer.
In vitro, the utilization of lactate acid was measured by lactate assay in cultured medium and the inhibition of LL/2 cell proliferation of four groups [control group, metformin group (1 mmol/L and 5 mmol/L), CHC group (5 mmol/L) and the combination group (metformin 5 mmol/L and CHC 5 mmol/L)] was detected in 24 h, 48 h, and their apoptosis in 24 h was also detected. In vivo, twenty eight C57BL/6 mice bearing LL/2 (5 x 10(5)) subcutaneous Lewis lung cancer on the right flank was established and then randomly assigned into four groups: control, metformin (200 mg/kg body mass in 0.1 mL i. g. with NS 0.1 mL i. p.), CHC (100 mg/kg body mass in 0.1 mL i.p. with NS 0.1 mL i. g. ) and the combination (metformin 200 mg/kg body mass in 0.1 mL i.g. with CHC 100 mg/kg body mass in 0.1 mL i. p.). Tumor volume was measured. The pathologic observation and apoptotic analysis of tumors was assessed by TUNEL assay.
Compared to the contorl, metformin or CHC alone, combination of two drugs leaded to a significant lactate acid production in cultured medium and the inhibition of LL/ 2 cell viability (P < 0.05). In vivo, the systemic administration of two drugs leaded to obvious retarded tumor growth compared with used alone in early stage (P < 0.05). The TUNEL assay showed the significantly increased number of apoptosis cells in tumor tissues from the combination group.
Combination of metformin and CHC transformed the lactic acid metabolism in LL/2 cells and induced cell apoptosis and showed the antitumor effect.
探讨二甲双胍与α-氰基-4-羟基肉桂酸（CHC，一种单羧酸转运蛋白1抑制剂）联合应用对Lewis肺癌的抗肿瘤作用。
体外实验中，通过检测培养基中乳酸利用情况来测定乳酸生成，检测四组[对照组、二甲双胍组（1 mmol/L和5 mmol/L）、CHC组（5 mmol/L）以及联合组（二甲双胍5 mmol/L和CHC 5 mmol/L）]在24 h、48 h时对LL/2细胞增殖的抑制情况，并在24 h时检测其凋亡情况。体内实验中，建立28只右侧胁腹皮下接种LL/2（5×10⁵）的C57BL/6小鼠Lewis肺癌模型，然后随机分为四组：对照组、二甲双胍组（200 mg/kg体重，0.1 mL灌胃，同时0.1 mL生理盐水腹腔注射）、CHC组（100 mg/kg体重，0.1 mL腹腔注射，同时0.1 mL生理盐水灌胃）以及联合组（二甲双胍200 mg/kg体重，0.1 mL灌胃，CHC 100 mg/kg体重，0.1 mL腹腔注射）。测量肿瘤体积。通过TUNEL法对肿瘤进行病理观察和凋亡分析。
与对照组、单独使用二甲双胍或CHC相比，两种药物联合使用导致培养基中乳酸生成显著增加，并抑制LL/2细胞活力（P<0.05）。在体内，与单独使用药物相比，两种药物全身给药在早期导致肿瘤生长明显延迟（P<0.05）。TUNEL法显示联合组肿瘤组织中凋亡细胞数量显著增加。
二甲双胍与CHC联合应用改变了LL/2细胞的乳酸代谢，诱导细胞凋亡，显示出抗肿瘤作用。
