New Players for Advanced Prostate Cancer and the Rationalisation of Insulin-Sensitising Medication

Figure 1

Therapeutic regimens combining insulin-sensitizing drugs and androgen-signalling inhibitors may be beneficial for treating prostate cancer progression following ADT. Androgen signalling is targeted using direct AR inhibitors. Bicalutamide (Casodex) and MDV3100 directly bind AR to prevent activity. Ketoconazole, abiraterone (Zitega), and TOK-001 have dual inhibition of CYP17A1 lyase/hydroxylase activity. In addition TOK-001 directly blocks AR activity. TAK-700 inhibits CYP17A1 lyase activity only and may not require concomitant control of rise in mineralocorticoids as is needed for abiraterone. Hyperinsulinaemia would be expected to increase insulin signalling in prostate cancer cells. Insulin can accelerate de novo androgen synthesis [153], which provides the AR with several suitable ligands (Key) and allows AR-mediated transcription of genes needed for CRPC progression. Additionally, insulin signalling may activate several AR-independent pathways (e.g., antiapoptosis and cell proliferation). Insulin-sensitizing drugs, such as metformin, orlistat, thiazolidinediones, and statins effectively block insulin-induced effects such as proliferation, lipid, and cholesterol synthesis and, hence, may be effective for the treatment of prostate cancer. The role of AR on AMPK-mediated cell response is still unclear and may be dependent on availability of cofactors (LKB1 versus CAMKK2).