Poli Giada, Cantini Giulia, Armignacco Roberta, Fucci Rossella, Santi Raffaella, Canu Letizia, Nesi Gabriella, Mannelli Massimo, Luconi Michaela
Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Oncotarget. 2016 Aug 2;7(31):49636-49648. doi: 10.18632/oncotarget.10421.
Adrenocortical carcinoma (ACC) is a rare heterogeneous malignancy with poor prognosis. Since radical surgery is the only available treatment, more specific and effective drugs are urgently required. The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment.This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R.Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%.Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo. Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC.
肾上腺皮质癌（ACC）是一种罕见的异质性恶性肿瘤，预后较差。由于根治性手术是唯一可用的治疗方法，因此迫切需要更具特异性和有效性的药物。抗糖尿病药物二甲双胍已被证明与几种实体瘤的癌症患病率和死亡率降低有关，这促使其可能用于ACC治疗。本文使用ACC细胞模型H295R评估了二甲双胍的体外和体内抗癌作用。二甲双胍治疗以剂量和时间依赖性方式显著降低细胞活力和增殖，并与ERK1/2和mTOR磷酸化/激活的显著抑制以及AMPK活性的刺激相关。二甲双胍还触发凋亡途径，表现为Bcl-2、HSP27、HSP60和HSP70的表达降低，以及膜联蛋白V的膜暴露增强，导致caspase-3凋亡效应器的激活。二甲双胍干扰支持肾上腺癌生长的IGF2/IGF-1R增殖自分泌环。最后，在通过皮下注射H295R细胞获得的ACC异种移植小鼠模型中，腹腔注射二甲双胍可抑制肿瘤生长，Ki67%的显著降低证实了这一点。我们的数据表明，二甲双胍在体外和体内均能抑制H295R细胞生长。需要进一步的临床前研究来验证二甲双胍对ACC患者的潜在抗癌作用。
