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

Abstract

This study was carried out to evaluate the antitumor activity of Metformin (Met) and its impending utility to potentiate the chemotherapeutic action of doxorubicin on 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5b]pyridine (PhIP)‐induced rat mammary carcinogenesis. Female Sprague –Dawley (SD) rats were divided into seven groups (n = 15 each). Mammary carcinogenesis was induced by the administration of PhIP at a dose of 75 mg/kg by gavage. Met treatment was 2 mg/ml in drinking water for 26 weeks started after the last PhIP dose. Doxorubicin (Dox) treatment started after one month of the last PhIP dose with a dose of 4 mg/kg, i.v. once per week for 4 weeks. Compared to the PhIP group, the latency period of tumors in the PhIP+Dox, PhIP+Met, and PhIP+Dox+Met groups were significantly increased and tumors’ incidences and multiplicities were significantly reduced. By immunohistochemistry, carcinomas from the combination treatment groups showed a significant decrease in the labeling indexes (LI%) of cellular proliferation and CD44 compared to the PhIP group while LI% for ERα was significantly decreased in all combination treatment groups compared to the PhIP‐administered group. Moreover, the quantitative mRNA expression of ERα was significantly decreased in mammary tumors from PhIP + Dox+Met combined group more than the PhIP + Dox group. However, mRNA expression of EGF was found significantly lower in all combination treatment groups compared to the PhIP group. These findings suggest that Metformin potentiate the antitumor efficacy of doxorubicin and had beneficial effects on PhIP‐induced mammary carcinogenesis through the prevention of cellular proliferation and mRNA expression of ERα and EGF.

Repurposing of atorvastatin and metformin denotes their individual and combined antiproliferative effects in non‐small cell lung cancer

“…Similarly, repurposing of Met for cancer treatment was suggested due to its direct effect on the AMPK pathway in tumor cells [32] and other metabolic-related mechanisms [33]. Despite the limited availability of clinical data supporting the use of statins or Met as monotherapy for cancer management, numerous investigations have evidenced their enhancing role with traditional chemotherapy [17]. Also, their beneficial combined effect was reported in many human disorders (exemplified in Table 4 [34][35][36][37][38][39][40][41][42][43][44][45]).…”

“…The antitumor activity of Met was attributed to both metabolic and epigenetic modulation of the cancer cells and the involvement of several signaling pathways like AMPK, AKT, and mTOR and activation of P53 [14, 15]. In the same manner, we previously found that the antiproliferative effect of Met was attributed to the dysregulation of AMPK and the associated oxidative stress in the mammary carcinoma rat model [16] and the drug enhanced the anticancer effect of Doxorubicin as well [17].…”

Metformin counters oxidative stress and mitigates adverse effects of radiation exposure: An overview

“…In contrast, MF protects only normal cells, without preventing damage to cancer cells [13][14][15]. It also shows synergism with some chemotherapeutic agents [110][111][112]. A review [14] is devoted to these properties of MF, considering the mechanisms of its action as a radioprotector with an anticancer effect.…”

“…An increase in tumor oxygenation is believed to be a possible radiosensitizing mechanism of MF [14,115], due to the reduction of oxygen consumption by mitochondria [13], and the induction of the oxygen effect [116]. It has been noted that MF affects even cancer stem cells that are chemoresistant and radioresistant, improving the prognosis of tumor treatment and reducing relapses [60,112].…”

The efficiency of amygdalin and doxorubicin combination on hepatocellular carcinoma and stromal myofibroblastic prostatic cells

“…It was used previously combined with resveratrol (Osman et al, 2012), superoxide dismutase (Villani et al, 1992), or other agents like amifostine, which is a broad spectrum cytoprotectant against radio and chemotherapy-related toxicities in vitro and in vivo while maintaining antitumor activity (Dragojevic-Simic et al, 2013). We have recently coupled Doxorubicin with metformin, a natural biguanide that is a type 2 anti-diabetes prescription, to reduce its side effects and boost its effectiveness against breast cancers in vivo (Salim et al, 2021).…”