The role of Metformin in colorectal cancer

Posted by Master, Doctor Mai Vien Phuong - Department of Examination & Internal Medicine - Vinmec Central Park International General Hospital

Many studies have shown that Metformin has an important role in the treatment of colorectal cancer. Metformin promotes cell cycle arrest at the G0/G1 phase in colorectal cancer cell lines.

Metformin promotes cell cycle arrest at the G0/G1 phase in colorectal cancer (colorectal cancer) cell lines. It also decreased the expression of c-Myc and induced IGF-1R upregulation. Thus, upregulation of the adenosine A1 receptor induces apoptosis. In addition, metformin enhances the activity of the Sprouty gene, which inhibits the growth of colon cancer. The combination of metformin with 5-FU has been studied in colorectal cancer cell line SW620 and in patients with type 2 diabetes mellitus. The study showed that metformin plus 5-FU treatment significantly inhibited SW620 cell proliferation compared with monotherapy.
In addition, examination of 86 colorectal cancer tissue samples obtained from patients with type 2 diabetes showed that treatment with metformin reduced the incidence of poorly differentiated tumors. Furthermore, a synergistic effect of 5-FU and metformin was observed in the 5-FU-resistant cell line and the radiation-induced metformin colorectal cancer cells, reducing the viability of the cells. ionization resistance. The association of oxaliplatin, 5-FU, and metformin also demonstrated superior anti-tumor activity in chemoresistant HT-29 and HCT-116 cells compared with the drugs alone. In 1977, it was first reported that phenformin inhibits metabolic inhibition in mice. Since then, several reports have demonstrated that metformin has both chemopreventive and therapeutic activities in animal models of colorectal cancer. For example, ApcMin/+ treated mice with metformin showed significantly smaller tumors, and carcinogenic animal models receiving metformin had reduced crypt malformations, suggesting a preventive effect. chemistry of metformin. Furthermore, the association of metformin with vitamin D3 demonstrated chemopreventive effects against 1,2-dimethylhydrazine (DMH)-induced colorectal cancer in mice and inflammation-associated colorectal cancer. colon by DMH-dextran sodium sulfate in rats. On the other hand, treatment with metformin, 5-FU and oxaliplatin showed superior anti-proliferative effects in SCID mice bearing colorectal cancer. In representative models, metformin suppressed tumor growth in patient-derived xenografts by up to 50%. In the same study, when metformin was combined with 5-FU, tumor growth was inhibited by up to 85%.

Numerous case-control and cohort studies as well as related meta-analyses have evaluated gastrointestinal cancer risk and metformin use. Specifically, most studies have reduced the risk of colorectal cancer, but have not found an association or increased risk of colorectal cancer in some studies. Cardel et al demonstrated, in a case-control study, a 17% reduction in the risk of colorectal cancer (OR: 0.83, 95% CI: 0.74-0.92) in treated patients. treated with metformin compared with patients not taking metformin, while Liu et al showed a 22% reduction in the risk of developing colorectal cancer. Importantly, the role of metformin in colorectal cancer prevention was covered in a prospective Japanese phase III trial demonstrating that a 1-year low dose of metformin reduced polyp formation and Colorectal adenomas in non-diabetic patients are at high risk for new polyps. However, further studies are needed to draw a firm conclusion.

Regarding colorectal cancer, a Korean study of 595 diabetic patients with colorectal cancer with clinical stages I to IV showed that patients using metformin had a better survival rate. Overall survival (overall survival rate) and cancer-specific survival were higher than in non-users. Accordingly, metformin use in 424 diabetic patients with colorectal cancer was associated with a treatment factor of 76.9 months compared with 56.9 months in patients not taking metformin (P = 0.048). After adjusting for possible confounding factors, the study found that patients with type 2 diabetes treated with metformin had a 30% increase in OS when compared with patients with type 2 diabetes treated with metformin. treated with other antidiabetic agents. Recent meta-analyses have demonstrated that metformin increases the OS of colorectal cancer patients, as well as reduces morbidity by 10%.

Tumor response to radiotherapy was improved with metformin in a retrospective Korean study evaluating patients with localized rectal cancer. Diabetic patients taking metformin had significantly higher levels of tumor regression 3-4 (P = 0.029) and lymph nodes (P = 0.006) compared with patients not taking the drug. However, disease-free survival (DFS) and overall survival were not affected. Also, a study of 482 patients examined the effect of metformin use on pathologic complete response rates (pCRs) and outcomes in patients receiving adjuvant chemotherapy for rectal cancer. colon. The rate of pCR was higher in patients with type 2 diabetes taking metformin (35%) than in patients without diabetes (16.6%) and patients with type 2 diabetes not taking metformin (7.5% ). In addition, significant increases in DFS and overall survival were found in patients receiving metformin. A phase II clinical trial involved the combination of metformin with 5-FU in patients with resistant colorectal cancer. It showed an 8-week disease control rate of 22%, with a median overall survival of 7.9 months and progression-free survival (PFS) of 1.8 months.

An authors' trial with a similar design that analyzed the combination of irinotecan with metformin showed a disease control rate of 41% and an overall survival rate of 8.2 months. A randomized trial including 40 patients with stage III colorectal cancer evaluated the use of metformin in the prevention of oxaliplatin-induced neuropathy. After the 12th cycle of the FOLFOX-4 regimen, there were fewer patients with grade 2 and 3 neuropathy in the metformin group than in the control group (60% vs 95%, P = 0.009). Furthermore, significantly higher total scores on the Ntx-12 questionnaire and pain scores were found in the metformin group. Serum concentrations of neurotensin and malondialdehyde were also significantly lower in the metformin group after 6 and 12 cycles. Furthermore, there are ongoing trials evaluating the role of metformin in colorectal cancer. The authors emphasize that, in the adjunctive setting, the phase 3 trial (NCT02614339) with high-risk stage II and stage III colorectal cancer aimed to evaluate the effects of metformin over 48 months on with disease-free survival.