二甲双胍治疗头颈部鳞状细胞癌机制的研究进展

doi:10.13701/j.cnki.kqyxyj.2020.12.003

摘要/Abstract

摘要： 头颈部鳞状细胞癌是全球第六大常见癌症,尽管治疗方法逐渐改善,其5年生存率仍仅为约63%。目前的治疗策略均带有不同程度的不良反应影响患者的生存质量。因此,找到一种毒性低、安全性高的治疗方法至关重要。二甲双胍是双胍类降糖药。研究表明,除降糖作用外,二甲双胍还可抑制多种癌症的发生与发展。二甲双胍抗头颈部鳞状细胞癌的机制可能包括降低胰岛素水平、抑制mTOR信号通路、抑制癌症干细胞、诱导细胞周期停滞并促进凋亡、免疫调节及增强辅助治疗效果等。本文结合现有文献就二甲双胍抗头颈部鳞状细胞癌可能的机制进行综述。

关键词: 头颈部鳞状细胞癌, 二甲双胍, 作用机制

Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth common cancer in the world. Although therapies have been improved gradually, the 5-year survival rate of patients with HNSCC remains stable at about 63%. Currently, all therapeutic strategies have severe side effects which reduced the quality of life. Therefore, it is essential to find a new therapy with lower toxicity and higher safety. Metformin is a hypoglycemic agent of biguanide class. Researches have shown that the metformin could inhibit the development and progression of HNSCC, in addition to reduce blood glucose. Mechanisms of metformin against HNSCC might include reducing the level of insulin, inhibiting the mTOR pathway and cancer stem cells, inducing cell cycle arrest, promoting apoptosis and immunomodulation, and enhancing the effect of adjuvant therapies. This article reviews the possible mechanism of metformin against HNSCC based on current available literatures.

Key words: head and neck squamous cell carcinoma, metformin, mechanism

张诗晨, 韩冰. 二甲双胍治疗头颈部鳞状细胞癌机制的研究进展[J]. 口腔医学研究, 2020, 36(12): 1091-1094.

ZHANG Shichen, HAN Bing. Research Progress on Mechanisms of Metformin in Treatment of Head and Neck Squamous Cell Carcinoma[J]. Journal of Oral Science Research, 2020, 36(12): 1091-1094.

参考文献

[1] Tan FH, Bai YC, Saintigny P, et al. mTOR signalling in head and neck cancer: heads up [J]. Cells, 2019, 8(4): 333.
[2] Lin YC, Wu MH, Wei TT, et al. Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress [J]. Oncotarget, 2014, 5(1): 298-308.
[3] Wu XY, Yeerna H, Goto Y, et al. Metformin inhibits progression of head and neck squamous cell carcinoma by acting directly on carcinoma-initiating cells [J]. Cancer Res, 2019, 79(17): 4360-4370.
[4] Sikka A, Kaur M, Agarwal C, et al. Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation [J]. Cell Cycle, 2012, 11(7): 1374-1382.
[5] Luo Q, Hu D, Hu S, et al. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma [J]. BMC Cancer, 2012, 12:517.
[6] Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, et al. Repurposing metformin for the prevention of cancer and cancer recurrence [J]. Diabetologia, 2017, 60(9): 1639-1647.
[7] Morales DR, Morris AD. Metformin in cancer treatment and prevention [J]. Annu Rev Med, 2015, 66:17-29.
[8] Rego DF, Pavan LMC, Elias ST, et al. Effects of metformin on head and neck cancer: A systematic review [J]. Oral Oncol, 2015, 51(5): 416-422.
[9] Tsou YA, Chang WD, Lu JJ, et al. The effect of metformin use on hypopharyngeal squamous cell carcinoma in diabetes mellitus patients [J]. BMC cancer, 2019, 19(1):862.
[10] Yen YC, Lin C, Lin SW, et al. Effect of metformin on the incidence of head and neck cancer in diabetics [J]. Head Neck-J Sci Spec, 2015, 37(9): 1268-1273.
[11] Figueiredo RAD, Weiderpass E, Tajara EH, et al. Diabetes mellitus, metformin and head and neck cancer [J]. Oral Oncol, 2016, 61:47-54.
[12] Stokes WA, Eguchi M, Amini A, et al. Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset [J]. Oral Oncol, 2018, 84:12-19.
[13] Hua F, Yu JJ, Hu ZW. Diabetes and cancer, common threads and missing links [J]. Cancer Lett, 2016, 374(1): 54-61.
[14] Vancura A, Bu PL, Bhagwat M, et al. Metformin as an anticancer agent [J]. Trends Pharmacol Sci, 2018, 39(10): 867-878.
[15] Madera D, Vitale-Cross L, Martin D, et al. Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3 [J]. Cancer Prev Res, 2015, 8(3): 197-207.
[16] Patel H, Younis RH, Ord RA, et al. Differential expression of organic cation transporter OCT-3 in oral premalignant and malignant lesions: potential implications in the antineoplastic effects of metformin [J]. J Oral Pathol Med, 2013, 42(3): 250-256.
[17] Vitale-Cross L, Molinolo AA, Martin D, et al. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions[J]. Cancer Prev Res (Phila), 2012, 5(4): 562-573.
[18] Siddappa G, Kulsum S, Ravindra DR, et al. Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells [J]. Mol Carcinogen, 2017, 56(11): 2446-2460.
[19] Gammon L, Mackenzie IC. Roles of hypoxia, stem cells and epithelial-mesenchymal transition in the spread and treatment resistance of head and neck cancer [J]. J Oral Pathol Med, 2016, 45(2): 77-82.
[20] Guimaraes TA, Farias LC, Santos ES, et al. Metformin increases PDH and suppresses HIF-1 alpha under hypoxic conditions and induces cell death in oral squamous cell carcinoma [J]. Oncotarget, 2016, 7(34): 55057-55068.
[21] Lindsay C, Kostiuk M, Conrad D, et al. Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells [J]. Mol Carcinogen, 2019, 58(11): 1946-1959.
[22] Curry J, Johnson J, Tassone P, et al. Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial [J]. Laryngoscope, 2017, 127(8): 1808-1815.
[23] Curry JM, Johnson J, Mollaee M, et al. Metformin clinical trial in HPV⁺ and HPV^- head and neck squamous cell carcinoma: impact on cancer cell apoptosis and immune infiltrate [J]. Front Oncol, 2018, 8:436.
[24] Miyauchi S, Kim SS, Pang J, et al. Immune modulation of head and neck squamous cell carcinoma and the tumor microenvironment by conventional therapeutics [J]. Clin Cancer Res, 2019, 25(14): 4211-4223.
[25] Yaniv B, Sadraei NH, Palackdharry S, et al. Metformin induces pro-tumorigenic cytokines and natural killer cells in patients with locally advanced head and neck squamous cell carcinoma [J]. Int J Radiat Oncol, 2018, 100(5): 1369.
[26] 梁兆佳,贺嘉忻,陈紫韵,等.二甲双胍对大鼠口腔黏膜溃疡的疗效之组织学评价[J].口腔医学研究,2019,35(7): 661-665.
[27] Amin D, Richa T, Mollaee M, et al. Metformin effects on FOXP3⁺ and CD8⁺ T cell infiltrates of head and neck squamous cell carcinoma [J]. Laryngoscope, 2020, 130(9):E490-E498.
[28] Skinner HD, Sandulache VC, Ow TJ, et al. TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence [J]. Clin Cancer Res, 2012, 18(1): 290-300.
[29] Woo SH, Yang LP, Chuang HC, et al. Down-regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy-induced senescence [J]. Head Neck-J Sci Spec, 2016, 38:E934-E940.
[30] Verma A, Rich LJ, Vincent-Chong VK, et al. Visualizing the effects of metformin on tumor growth, vascularity, and metabolism in head and neck cancer [J]. J Oral Pathol Med, 2018, 47(5): 484-491.
[31] Gulati S, Desai J, Palackdharry SM, et al. Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer [J]. Cancer, 2020, 126(2): 354-362.
[32] Qi XF, Xu WG, Xie JQ, et al. Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-kappa B/HIF-1 alpha signal axis [J]. Sci Rep, 2016, 6:35788.
[33] Song C, Tang C, Xu W, et al. Hypoxia-targeting multifunctional nanoparticles for sensitized chemotherapy and phototherapy in head and neck squamous cell carcinoma [J]. Int J Nanomedicine, 2020, 15:347-361.
[34] Kuo SZ, Honda CO, Li WT, et al. Metformin results in diametrically opposed effects by targeting non-stem cancer cells but protecting cancer stem cells in head and neck squamous cell carcinoma [J]. Int J Mol Sci, 2019, 20(1):193.
[35] Zhang J. Effect of adriamycin combined with metformin on biological function of human tongue cancer SSC-15 cells [J]. Oncol Lett, 2019, 17(6): 5674-5680.
[36] Ajzashokouhi AH, Bostan HB, Jomezadeh V, et al. A review on the cardioprotective mechanisms of metformin against doxorubicin [J]. Hum Exp Toxicol, 2020, 39(3):237-248.
[37] Harada K, Ferdous T, Harada T, et al. Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma [J]. Int J Oncol, 2016, 49(1): 276-284.
[38] Mynhardt C, Damelin LH, Jivan R, et al. Metformin-induced alterations in nucleotide metabolism cause 5-fluorouracil resistance but gemcitabine susceptibility in oesophageal squamous cell carcinoma [J]. J Cell Biochem, 2018, 119(1): 1193-1203.
[39] Yin XT, Han SW, Song CH, et al. Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells [J]. Cell Oncol, 2019, 42(4): 459-475.
[40] Yin XT, Wei Z, Song CH, et al. Metformin sensitizes hypoxia-induced gefitinib treatment resistance of HNSCC via cell cycle regulation and EMT reversal [J]. Cancer Manag Res, 2018, 10:5785-5798.