tenovin-1 and Prostatic-Neoplasms--Castration-Resistant

Since altered energy metabolism is a hallmark of cancer, many drugs targeting metabolic pathways are in active clinical trials. The tumor suppressor p53 is often inactivated in cancer, either through downregulation of protein or loss-of-function mutations. As such, stabilization of p53 is considered as one promising approach to treat those cancers carrying wild type (WT) p53. Herein, SIRT1 inhibitor Tenovin-1 and polo-like kinase 1 (Plk1) inhibitor BI2536 were used to stabilize p53. We found that both Tennovin-1 and BI2536 increased the anti-neoplastic activity of metformin, an inhibitor of oxidative phosphorylation, in a p53 dependent manner. Since p53 has also been shown to regulate metabolic pathways, we further analyzed glycolysis and oxidative phosphorylation upon drug treatments. We showed that both Tennovin-1 and BI2536 rescued metformin-induced glycolysis and that both Tennovin-1 and BI2536 potentiated metformin-associated inhibition of oxidative phosphorylation. Of significance, castration-resistant prostate cancer (CRPC) C4-2 cells show a much more robust response to the combination treatment than the parental androgen-dependent prostate cancer LNCaP cells, indicating that targeting energy metabolism with metformin plus p53 stabilizers might be a valid approach to treat CRPC carrying WT p53.

Topics: Acetanilides; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Male; Metformin; Mitochondria; Mitosis; Oxidative Phosphorylation; Polo-Like Kinase 1; Prostate; Prostatic Neoplasms, Castration-Resistant; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Signal Transduction; Sirtuin 1; Thiourea; Tumor Suppressor Protein p53