Diclofenac and metformin synergistic dose dependent inhibition of hamster fibrosarcoma, rescued with mebendazole

Dušica J Popović; Kosta J Popović; Dejan Miljković; Jovan K Popović; Dušan Lalošević; Mihalj Poša; Zana Dolićanin; Ivan Čapo

doi:10.1016/j.biopha.2023.115528

Diclofenac and metformin synergistic dose dependent inhibition of hamster fibrosarcoma, rescued with mebendazole

Biomed Pharmacother. 2023 Nov:167:115528. doi: 10.1016/j.biopha.2023.115528. Epub 2023 Sep 20.

Authors

Dušica J Popović¹, Kosta J Popović², Dejan Miljković³, Jovan K Popović⁴, Dušan Lalošević³, Mihalj Poša², Zana Dolićanin¹, Ivan Čapo³

Affiliations

¹ Department of Biomedical Sciences, State University of Novi Pazar, Vuka Karadžića 9, 36300 Novi Pazar, Serbia.
² Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
³ Department of Histology and Embryology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia.
⁴ Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia; Academy of Medical Sciences of the Serbian Medical Society, 19 George Washington str.,11000 Belgrade, Serbia. Electronic address: jovapopmf@gmail.com.

PMID: 37738800
DOI: 10.1016/j.biopha.2023.115528

Abstract

We examined whether combinig diclofenac and metformin in doses equivalent to human doses would synergize their anticancer activity on fibrosarcoma inoculated to hamsters and in vitro. Rescue experiment was performed to examine whether the prosurvival NF-κB stimulation by mebendazole can reverse anticancer effects of the treatment. BHK-21/C13 cell culture was subcutaneously inoculated to Syrian golden hamsters randomly divided into groups (6 animals per group): 1) untreated control; treated daily with 2) diclofenac; 3) metformin; 4) combinations of diclofenac and metformin at various doses; 5) combination of diclofenac, metformin and mebendazole; 6) mebendazole. Dose response curves were made for diclofenac and metformin combination. Tumor growth kinetics, biophysical, pathological, histological and immunohistochemical characteristics of excised tumors and hamster organs as well as biochemical and hematological blood tests were compared among the groups. Single treatments had no anticancer effects. Diclofenac (60 mg/kg/day) exhibited significant (P < 0.05) synergistic inhibitory effect with metformin (500 mg/kg/day) on all tumor growth parameters, without toxicity and influence on biochemical and hematological blood tests. The same results were obtained with double doses of diclofenac and metformin combination. The addition of mebendazole to the diclofenac and metformin combination rescued tumor expansion. Furthermore, diclofenac with metformin demonstrated antiproliferative effects in hamster fibrosarcoma BHK-21/C13, human lung carcinoma A549 (CCL-185), colon carcinoma HT-29 (HTB-38) and cervical carcinoma HeLa (CCL-2) cell cultures, with markedly lower cytotoxicity in the normal fetal lung MRC-5 cells. In conclusion, diclofenac and metformin combination may be recommended for potential use in oncology, due to synergistic anticancer effect in doses achievable in humans.

Keywords: Diclofenac; Fibrosarcoma; Hamsters; Mebendazole; Metformin; NF-κB.