Nangia-Makker Pratima, Yu Yingjie, Vasudevan Anita, Farhana Lulu, Rajendra Sindhu G, Levi Edi, Majumdar Adhip P N
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan, United States of America ; Department of Internal Medicine, Wayne State University, Detroit, Michigan, United States of America.
PLoS One. 2014 Jan 20;9(1):e84369. doi: 10.1371/journal.pone.0084369. eCollection 2014.
Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties. However, most of the studies to evaluate therapeutic efficacy of metformin have been on primary cancer. No information is available whether metformin could be effectively used for recurrent cancer, specifically colorectal cancer (CRC) that affects up to 50% of patients treated by conventional chemotherapies. Although the reasons for recurrence are not fully understood, it is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs). Therefore, development of non-toxic treatment strategies targeting CSCs would be of significant therapeutic benefit. In the current investigation, we have examined the effectiveness of metformin, in combination with 5-fluorouracil and oxaliplatin (FuOx), the mainstay of colon cancer therapeutics, on survival of chemo-resistant colon cancer cells that are highly enriched in CSCs/CSLCs. Our data show that metformin acts synergistically with FuOx to (a) induce cell death in chemo resistant (CR) HT-29 and HCT-116 colon cancer cells, (b) inhibit colonospheres formation and (c) enhance colonospheres disintegration. In vitro cell culture studies have further demonstrated that the combinatorial treatment inhibits migration of CR colon cancer cells. These changes were associated with increased miRNA 145 and reduction in miRNA 21. Wnt/β-catenin signaling pathway was also down-regulated indicating its pivotal role in regulating the growth of CR colon cancer cells. Data from SCID mice xenograft model of CR HCT-116 and CR HT-29 cells show that the combination of metformin and FuOX is highly effective in inhibiting the growth of colon tumors as evidenced by ∼ 50% inhibition in growth following 5 weeks of combination treatment, when compared with the vehicle treated controls. Our current data suggest that metformin together with conventional chemotherapy could be an effective treatment regimen for recurring colorectal cancer (CRC).
越来越多的证据表明，二甲双胍这种双胍类抗糖尿病药物具有抗癌特性。然而，大多数评估二甲双胍治疗效果的研究都集中在原发性癌症上。目前尚无关于二甲双胍是否可有效用于复发性癌症的信息，特别是对于高达50%接受传统化疗的患者会发生的结直肠癌（CRC）。尽管复发原因尚未完全明确，但一般认为这是由于化疗耐药的癌症干细胞/干细胞样细胞（CSCs/CSLCs）重新出现所致。因此，开发针对CSCs的无毒治疗策略将具有显著的治疗益处。在当前的研究中，我们研究了二甲双胍与结肠癌治疗的主要药物5-氟尿嘧啶和奥沙利铂（FuOx）联合使用，对高度富集CSCs/CSLCs的化疗耐药结肠癌细胞存活的影响。我们的数据表明，二甲双胍与FuOx协同作用，（a）诱导化疗耐药（CR）的HT-29和HCT-116结肠癌细胞死亡，（b）抑制结肠球形成，（c）增强结肠球解体。体外细胞培养研究进一步证明，联合治疗可抑制CR结肠癌细胞的迁移。这些变化与miRNA水平的改变有关，miRNA水平的改变表现为miRNA 145增加和miRNA 21减少。Wnt/β-连环蛋白信号通路也被下调，表明其在调节CR结肠癌细胞生长中起关键作用。来自CR HCT-116和CR HT-29细胞的SCID小鼠异种移植模型的数据表明，与溶媒处理的对照组相比，二甲双胍和FuOX联合使用在抑制结肠肿瘤生长方面非常有效，联合治疗5周后肿瘤生长抑制约50%。我们目前的数据表明，二甲双胍与传统化疗联合使用可能是复发性结直肠癌（CRC）的有效治疗方案。
