Figure 4.
Effect of bortezomib and metformin on tumor volume (TV) and overall survival. MM.1S cells (3 × 106/injection) were subcutaneously placed in the flanks of 5-week-old nude NCr nu/nu female mice. Mice were then randomly distributed into four groups (10/group) and after the formation of palpable tumors treatment was commenced. Groups received intravenous injection of either vehicle (phosphate-buffered saline containing 10% dimethyl sulfoxide (DMSO)) or bortezomib (0.5 mg/kg in phosphate-buffered saline, 10% DMSO) administered with or without metformin (600 μg/ml diluted in drinking water that contained 5% dextrose). Metformin was administered throughout treatment and vehicle or bortezomib administered on days 1–4. TVmeasurements were made using a vernier caliper and calculated using the formula: TV=0.5(a × b2) where a is the long diameter and b the short diameter. Mice were euthanized when tumors reached 2 cm3, became ulcerated or elicited neurologic or musculoskeletal complications that limited mobility and feeding. TV was evaluated from the first day of treatment. Shown is the average of replicate measurements. (b) Kaplan–Meier survival curves after treated with either vehicle, metformin, bortezomib or both.