Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway

Abstract

Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.

Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer

“…Furthermore, metformin combined with current chemotherapies in murine xenograft models of ovarian cancer (17,18) and other cancers (lung, bladder, colon, breast, etc.) has been confirmed to synergistically repress tumor growth (19)(20)(21)(22). Initial explanations attributed its effect to directly decreasing energy consumption, fatty acid, and protein synthesis via the mediation of AMPK/mTOR signaling and indirect restraint of the PI3K/AKT cascade (23)(24)(25).…”

Metformin potentiates the chemotherapeutic effects of doxorubicin on 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5b] pyridine‐induced Mammary Carcinoma in rats

“…These results were in accordance with Ghoshal et al [18] who found that female SD rats that treated orally with PhIP showed different phenotypes of mammary tumors including intraductal carcinoma (papillary, cribriform, and comedo type) and tubular adenocarcinoma. A study by El‐Ashmawy et al [35] demonstrated that Met alone or in combination with Dox showed enhanced apoptosis and absence of necrosis in tumor tissue of co‐treatment group.…”

Anticancer effect of metformin against 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine-induced rat mammary carcinogenesis is through AMPK pathway and modulation of oxidative stress markers

“…Our results were in accordance with Ghoshal et al 21 who found that female SD rats that treated orally with PhIP showed different phenotypes of mammary tumors including intraductal carcinoma (papillary, cribriform, and comedotype) and tubular adenocarcinoma. In addition, a study by El-Ashmawy et al 28 demonstrated that metformin alone or in combination with doxorubicin reduced the tumor volume of solid Ehrlich carcinoma mice, and this effect was mediated through AMPK pathway.…”