Metformin as an Adjuvant Drug against Pediatric Sarcomas: Hypoxia Limits Therapeutic Effects of the Drug

Abstract

Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.

Effect of metformin and adriamycin on transplantable tumor model

“…Moreover, 4 metformin has been shown to improve endothelial function, decrease inflammatory response, and regulate immune functions which have a major role in the pathogenesis of cancer (Li, 2011). Also, metformin was proven to inhibit P-glycoprotein expression via the nuclear factor-κB pathway through AMP-kinase activation (Garofalo et al, 2013;Rosilio et al, 2014).…”

Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells

“…Other tumor-microenvironmental factors such as intratumoral pH, glutamine concentration, and oxygen tension are likely to influence the in vivo efficacy of metformin [38, 39]. Like metformin treatment, hypoxia shifts cellular metabolism towards glycolysis.…”

“…Like metformin treatment, hypoxia shifts cellular metabolism towards glycolysis. This effect could either lead to synergy or reduce metformin effects, as shown in a sarcoma cell line model [39]. However, the sarcoma cell line study CoCl 2 was used as a hypoxia mimetic in a short-term assay.…”

6-Gingerol inhibits osteosarcoma cell proliferation through apoptosis and AMPK activation

“…These findings provide evidence that AMPK may serve as a potential anti-tumor target for treating different carcinomas. Recently, AMPK activators have been reported to act in a combinational fashion to exert anti-cancer activity against sarcoma [11,12]. Nevertheless, the role of AMPK activation in the oncogenesis of osteosarcoma is sketchy.…”