Saif Muhammad Wasif, Rajagopal Shrikar, Caplain Jennifer, Goodman Martin D, Popowich Daniel, Orkin Bruce A, Tsichlis Philip N, Martell Robert
Northwell Health Cancer Institute, Lake Success, NY 11042, USA.
Cancer Med J. 2021 Sep;4(Suppl 4):1-10. Epub 2021 Feb 19.
The cancer stem cell (CSC) hypothesis of tumor genesis suggests that unlike most cancer cells within tumor CSC resist chemotherapy and can regenerate various cell types in tumor thereby causing relapse. Hence drugs that selectively target CSC may offer great promise for cancer therapy especially when combined with chemotherapy. Current treatment options for colorectal cancer (CRC) and other gastrointestinal (GI) tumors rely on combination of surgical resection, cytotoxic and targeted drugs. Recent findings showed that metformin, an ant diabetic drug was associated with a significantly lower risk of CRC (0.63 [0.47 - 0.84]; = 0.002) in patients with type 2 diabetes. We therefore hypothesize that administration of metformin will reduce CSC.
Patients with CRC and other GI cancers undergoing resection were enrolled. Metformin was administered at 500 mg orally twice daily for up to 14 days and terminated 24 hours, prior to planned surgery. Both tumor and normal tissue was procured. Adverse events (AEs) were graded according to NCI CTCAE Version 3.0. Primary objective was to establish the safety of administering metformin prior to resection. Secondary objective was to evaluate the effects of metformin on the expression of CSC markers by measuring relative mRNA levels of CD133, OCT4 and NANOG by RT-PCR and immunohistochemistry.
A total of 10 patients (4 Male; 6 Female) received metformin. Grade 3 AEs included anemia, hypoalbuminemia, alanine aminotransferase elevation, abdominal pain and nausea but none of these were related to metformin. No hypoglycemia and lactic acidosis were observed. No unexpected post-operative complications were witnessed. Comparison of markers of CCSC results showed that expression of CD133, OCT4 and NANOG expression were decreased following metformin.
Our pilot study showed feasibility of metformin before surgery in GI cancers and indicated impact on CSC. This preliminary data warrants further investigation in a larger randomized placebo-control study to assess these markers and their correlation with survival.
肿瘤发生的癌症干细胞（CSC）假说表明，与肿瘤内的大多数癌细胞不同，CSC对化疗具有抗性，并且可以在肿瘤中再生各种细胞类型，从而导致复发。因此，选择性靶向CSC的药物可能为癌症治疗带来巨大希望，尤其是与化疗联合使用时。目前，结直肠癌（CRC）和其他胃肠道（GI）肿瘤的治疗选择依赖于手术切除、细胞毒性药物和靶向药物的联合使用。最近的研究发现，二甲双胍这种抗糖尿病药物与2型糖尿病患者患CRC的风险显著降低有关（0.63 [0.47 - 0.84]；P = 0.002）。因此，我们假设服用二甲双胍会减少CSC。
纳入接受手术切除的CRC和其他GI癌症患者。二甲双胍以500毫克口服，每日两次，服用长达14天，并在计划手术前24小时停药。采集肿瘤组织和正常组织。不良事件（AE）根据美国国立癌症研究所（NCI）不良事件通用术语标准（CTCAE）第3.0版进行分级。主要目标是确定在切除术前服用二甲双胍的安全性。次要目标是通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学测量CD133、OCT4和NANOG的相对mRNA水平，评估二甲双胍对CSC标志物表达的影响。
共有10名患者（4名男性；6名女性）接受了二甲双胍治疗。3级AE包括贫血、低白蛋白血症、丙氨酸转氨酶升高、腹痛和恶心，但这些均与二甲双胍无关。未观察到低血糖和乳酸性酸中毒。未出现意外的术后并发症。CSC标志物结果比较显示，服用二甲双胍后，CD133、OCT4和NANOG的表达降低。
我们的初步研究表明，在GI癌症手术前使用二甲双胍具有可行性，并表明其对CSC有影响。这些初步数据值得在更大规模的随机安慰剂对照研究中进一步调查，以评估这些标志物及其与生存的相关性。
