Metformin displaysin vitroandin vivoantitumor effect against osteosarcoma

Abstract

PurposePatients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research.MethodsWe evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL) ad libitum. Tumor volume was measured every 3–4 days for a period of 4 weeks.ResultsMetformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potent in vivo antitumor effects.ConclusionFurther studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma.

Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma

“…In OS cell lines, metformin exhibited a dose-and timedependent inhibition of cell cycle, tumor proliferation, and invasion in vitro and in xenograft models, as shown by three different research groups (Ko et al, 2016) (B. Li et al, 2020a (Li et al, 2018). In these studies, high concentration (mM range, far higher than doses used in patients) of metformin could trigger cell cycle arrest by G2/M accumulation, which was confirmed by the upregulation of cell cycle-related protein Cyclin D1.…”

In Vitro and In Ovo Evaluation of the Potential Hepatoprotective Effect of Metformin

“…Thus, for evaluating the effect on cell viability, the hepatocyte cell line-HepaRG-was selected, in which five concentrations of Met (0.5, 1, 1.5, 2 and 2.5 mM) were tested for two time intervals, of 24 and 72 h. Concentrations and their equivalents in mg: 0.173, 0.346, 0.519, 0.692 and 0.865 mg) were selected after extensive evaluation of the literature on in vitro testing of Metformin [32][33][34][35][36]. Additionally, when selecting the tested concentrations, an estimated calculation was made to correlate the in vitro concentrations and the corresponding in vivo doses by applying the formulas described by Levy [37].…”

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

“…Metformin an FDA-approved drug regulates glucose metabolism and inhibits complex 1, it is currently repurposed as an antineoplastic agent [16,17,19,[44][45][46][47][48][49]. Similarly, proteasome inhibitors (MG132 and PS341) [27] were used to target proteasome upregulation in ECM detached cells.…”