A novel therapeutic approach to colorectal cancer in diabetes: role of metformin and rapamycin

Abstract

The link between colorectal cancer (CRC), diabetes mellitus (DM) and inflammation is well established, and polytherapy, including rapamycin, has been adopted. This study is a novel approach that aimed at assessing the effect of a combination therapy of metformin and rapamycin on the control or prevention of CRC in diabetic animals, in presence or absence of probiotics. Fifty NOD/SCIDs male mice developed xenograft by inoculating HCT116 cells. They were equally divided into diabetics (induced by Streptozotocin) and non-diabetics. Metformin was given in drinking water, whereas rapamycin was administered via intra-peritoneal injections. Probiotics were added to the double therapy two weeks before the sacrifice. Assessment was performed by clinical observation, histological analysis, Reactive oxygen species (ROS) activities and molecular analysis of Interleukin 3 and 6, Tumor Necrosis Factor alpha, AMP-activated protein Kinase and the mammalian target of rapamycin. Decreases in the level of tumorigenesis resulted, to various extents, with the different treatment regimens. The combination of rapamycin and metformin had no significant result, however, after adding probiotics to the combination, there was a marked delay in tumor formation and reduction of its size, suppression of ROS and a decrease in inflammatory cytokines as well as an inhibition of phosphorylated mTOR. Existing evidence clearly supports the use of rapamycin and metformin especially in the presence of probiotics. It also highlighted the possible mechanism of action of the 2 drugs through AMPK and mTOR signaling pathways and offered preliminary data on the significant role of probiotics in the combination. Further investigation to clarify the exact role of probiotics and decipher in more details the involved pathways is needed.

Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects

“…Combination with IR inhibits DNA repair protein that increases radiosensitivity in HCT116 p53 − / − xenografts mice.Metformin (alone, 150 mg/kg body weight) and with rapamycin (intraperitoneal, 0.5 mg/kg body weight) modulates AMPK and mTOR modulation, inhibits tumor volume in HCT116-xenorafted NOD/SCIDs male mice. The addition of probiotic mixture inhibited the intracellular ROS, IL-3, and IL-6 levels which further reduced the tumor volume by 40%.[44, 48, 63]DMH-induced CRC in diabetic and non-diabetic miceSingle (100 or 200 mg/kg) and combination of metformin and/or oxaliplatin inhibited angiogenesis and tumor proliferation in DMH-induced CRC diabetic and non-diabetic mice by suppressing tumor angiogenesis and cell proliferation by reducing serum VEGF level and intratumoral IGFR-I.[61]PDX- female SCID miceMetformin (150 mg/kg, 24 days) suppresses tumor growth (by 50%) in PDX CRC-female SCID mice. Combination with 5-FU (IP, 25 mg/kg) inhibited tumor growth (up to 85%).…”

Metformin and Probiotics in the Crosstalk between Colitis-Associated Colorectal Cancer and Diabetes in Mice

“…It has also been suggested that there might be an inflammation-triggering effect of the intestinal microbiota in the development of autoimmune diabetes [ 11 , 12 ]. Previous publications from our group and others supported the possible pathogenic links among CRC and diabetes, whereby an altered glucose metabolism, an oxidative stress, and a chronic inflammatory state, triggered by an imbalance in the intestinal microbiota, are potential mediators [ 3 , 13 , 14 ].…”

“…A series of recent publications support the fact that inflammation paralleled with dysfunctional interactions between gut microbiota and the mucosal immune system are well defined risk factors for IBD, CRC, and other inflammatory and metabolic diseases such as diabetes [ 3 , 5 , 13 ]. On this basis, the recommendation of probiotics as part of the management protocols has been widely considered [ 23 , 24 ].…”

Is Metformin a Treatment Opportunity for Colorectal Cancer?

“…(29) Geagea et al showed the synergetic effects of metformin and rapamycin in association with the probiotics caused to decreased expression of early lesions in CRC such as ACF in mice with xenografts. (30)…”