Experimental evaluation of the effects of anticancer modulation therapy on MAPK/PI3K/AKT/mTOR/NF-κB signaling with non-toxic drugs

Abstract

Introduction/Objective. Large diversity in molecular mechanisms of cancer regulation allows some marketed pleiotropic non-oncological non-toxic pharmaceuticals to be used in oncology, which reduces duration and cost of novel anticancer treatment research. To date, there are no published in vivo results on anticancer effects of certain combinations of non-oncological pleiotropic drugs (disulfiram, metformin, deoxycholic acid, mebendazole) that influence MAPK/PI3K/AKT/mTOR/NF-?B signaling. Methods. The anticancer effects of certain aforementioned repurposed drugs combinations, < 50 % LD50 (equivalent to the usual human dose) were assessed by fibrosarcoma growth kinetics (measured daily in vivo by calipers) and tumor proliferation (Ki-67, PCNA), neoangiogenesis (CD34, CD31), glucose metabolism (GLUT1), NO metabolism (iNOS) and apoptosis (COX4, cytochrome C) in hamsters, randomly allocated to control and experimental groups (six animals per group). The animals were sacrificed 19 days after BHK-21/C13 tumor inoculation. The tumors were excised, measured, and blood was collected. Biophysical, pathohistological, toxicological, hematological, and biochemical analyses were performed. Results. Disulfiram with metformin, disulfiram with deoxycholic acid and deoxycholic acid with metformin are the combinations that have shown significant antitumor effects on the fibrosarcoma growth kinetics and tumor immunohistochemical markers in hamsters (p < 0.05). All used drugs in efficacious combinations can inhibit MAPK/PI3K/AKT/mTOR/NF-?B signaling. The addition of NF-?B stimulator mebendazole to effective two-drug combinations rescued cancer growth, indicating that these pathways may be responsible for antitumor action. Conclusion. Combinations of non-oncological drugs: disulfiram with metformin, disulfiram with deoxycholic acid and deoxycholic acid with metformin have the potential to be used as effective non-toxic adjuvant anticancer therapy in oncology.