Multiple myeloma (MM) is a fatal haematological malignancy characterised by accumulation of malignant plasma cells in the bone marrow (BM), and severe lytic bone disease. Metformin is widely prescribed in diabetes, and is associated with improved outcomes in diabetic patients with MM, suggesting a potential anti-myeloma effect of metformin. The aim of the current study was to investigate the effect of metformin within the myeloma-bone microenvironment in vitro and in vivo. C57Bl/KaLwRij mice were inoculated with 5TGM1MM cells and treated with metformin either from time of tumour inoculation (continuous) or from time of established tumour (delayed). MM-bearing mice treated with metformin exhibited a decrease in myeloma-specific serum IgG2bk concentrations as compared to control (control, 4.29 mg/ml±0.3 mg/ml; metformin-continuous, 1.51 mg/ml±0.6 mg/ml, P<0.001; metformin-delayed, 0.7 mg/ml±0.7 mg/ml, P<0.001). MicroCT analysis demonstrated a significant decrease in osteolytic lesion number in MM-bearing mice treated with metformin (control, 26±3.6; metformin-continuous, 11.4±0.7, P<0.001; metformin-delayed, 9±1.5, P<0.01). Metformin induced a dose-dependent decrease in MM cell viability. MM cell lines exhibited a differential sensitivity to metformin; RPMI 8226 cells had highest basal metabolic activity and sensitivity to metformin. Metformin treatment of MM cells activated AMPK, decreased IGF1 gene expression and induced apoptosis, detected by an increase in cleaved caspase-3 and PARP. Metformin had no effect on BM stromal cell (BMSC) viability. Direct contact of MM cells with BMSCs decreased the anti-MM effect of metformin. BMSC-conditioned media (CM) had a protective effect against the anti-MM effects of metformin at 24 h that was lost by 72 h. In contrast, BMSC CM protected against the anti-MM effects of the proteasome inhibitor bortezomib at all time points. Our studies demonstrate a strong anti-tumour effect of metformin in the MM-bone microenvironment, suggesting that metformin may be effective for the treatment of MM and the associated bone disease.
Disclosure: The authors declared no competing interests. This work was supported by NIH/NCI R01 CA137116.