JCEM：二甲双胍可抑制分化型甲状腺癌生长

临床试验显示二甲双胍增加癌症患者系统性治疗的疗效。为了验证分化型甲状腺癌（DTC）常规治疗的疗效在糖尿病患者中是否受到二甲双胍治疗的影响，来自美国国防医科大学的Vasyl Vasko教授及其团队进行了一项研究，该研究发现在肿瘤比较小的患者使用二甲双胍治疗，提示通过二甲双胍可抑制肿瘤生长。在糖尿病患者中，缺少二甲双胍治疗是完全缓解（CR）可能性减少和无进展生存期缩短风险增加的独立因素。体外数据提示在DTC细胞中，p70S6K/PS6可能是二甲双胍的分子靶位。该研究结果在线发表在2013年5月24日的《临床内分泌代谢杂志》（The journal of clinical endocrinology & metabolism）上。

该研究中，比较使用二甲双胍治疗的糖尿病患者（MF+组，34例）与未使用二甲双胍治疗的糖尿病患者（MF-组，21例）、以及非糖尿病患者组（C组，185例）之间的完全缓解率。同时在体外检验二甲双胍对DTC细胞的影响。

该研究结果表明，三组间在年龄、性别、体重指数（BMI）、糖尿病管理、多病灶肿瘤生长的频率、甲状腺外扩散、局部和远处转移方面具有可比性。MF+组与MF-组和C组相比，肿瘤大小显著缩小（1.37±0.97cm vs 2.44±1.49cm vs 2.39±1.73cm，P=0.026）。多变量模型显示甲状腺外扩散（P=0.018）、远处转移（P＜0.0001）、以及糖尿病缺乏二甲双胍治疗（p P＜0.0001）降低CR的可能性。COX风险模型显示年龄（P=0.025）、局部转移（P=0.022）、远处转移（P=0.003）和糖尿病缺乏二甲双胍治疗（P=0.014）与无进展生存期（PFS）缩短风险增加有关。体外数据显示二甲双胍抑制癌细胞生长，激活CAMP诱导蛋白激酶（AMPK）和下调p70S6K/pS6。二甲双胍加强H₂O₂诱导的AMPK激活，但减弱pERK和p70S6K。MF+患者的肿瘤与MF-组相比，显示低水平磷酸化p70S6K。

该研究发现，在肿瘤比较小的患者使用二甲双胍治疗，提示通过二甲双胍可抑制肿瘤生长。在糖尿病患者中，缺少二甲双胍治疗是完全缓解（CR）可能性减少和无进展生存期缩短风险增加的独立因素。体外数据提示在DTC细胞中，p70S6K/PS6可能是二甲双胍的分子靶位。

Treatment with Metformin is Associated with Higher Remission Rate in Diabetic Patients with Thyroid Cancer.
Abstract
Context:Clinical trials demonstrated that metformin increases the efficiency of systemic therapy in cancer patients.Objective:We examined whether the efficacy of conventional treatment of differentiated thyroid cancer (DTC) is affected by therapy with metformin in diabetic patients.Design:We compared the rate of complete response (CR) between diabetics treated (Group MF+, n=34), or non-treated with metformin (Group MF-, n=21) and control non-diabetic patients (Group C, n=185). We also examined the effects of metformin on DTC cells in vitro.Results:The groups were comparable in terms of age, sex, BMI, diabetes management, frequencies of multifocal tumor growth, extrathyroidal extension, loco-regional and distant metastases. Tumor size was significantly smaller in MF+ compared with MF- and C groups (1.37±0.97 cm vs 2.44±1.49 cm vs 2.39±1.73 cm, p=0.026). A multivariate model revealed that extrathyroidal extension (p=0.018), distant metastases (p<0.0001) and lack of treatment with metformin of diabetics (p<0.0001) decreased the likelihood of CR. A Cox hazards model revealed that age (p=0.025), loco-regional metastases (p=0.022), distant metastases (p=0.003) and lack of treatment with metformin of patients with diabetes (p=0.014) are associated with increased risk for shortened progression free survival (PFS).In vitro data revealed that metformin inhibited cancer cells growth, activated cAMP-inducible protein kinase (AMPK) and down-regulated p70S6K/pS6. Metformin potentiated H2O2-inducible activation of AMPK but attenuated pERK and p70S6K. Tumors from MF+ patients demonstrated lower level of phospho-p70S6K compared with MF- group.Conclusions:Tumor size is smaller in patients treated with metformin suggesting inhibition of tumor growth by the drug. Among diabetics, absence of metformin therapy is an independent factor for decreased likelihood of CR and increased risk of shorter PFS. In vitro data suggest that p70S6K/pS6 is likely a molecular target of metformin in DTC cells.

原始出处：
Klubo-Gwiezdzinska J, Costello J Jr, Patel A, Bauer A, Jensen K, Mete M, Burman KD, Wartofsky L, Vasko V.Treatment with Metformin is Associated with Higher Remission Rate in Diabetic Patients with Thyroid Cancer.  Clin Endocrinol Metab. 2013 May 24.

此前相关研究：
Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A, Burman KD, Wartofsky L, Vasko V.Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer. 2012 May 24;19(3):447-56.

Chen G, Xu S, Renko K, Derwahl M.Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab. 2012 Apr;97(4):E510-20

Rezzónico J, Rezzónico M, Pusiol E, Pitoia F, Niepomniszcze H.Metformin treatment for small benign thyroid nodules in patients with insulin resistance. Metab Syndr Relat Disord. 2011 Feb;9(1):69-75.