New insights into molecular mechanisms of rosiglitazone in monotherapy or combination therapy against cancers.

Rosiglitazone (ROSI), a member of thiazolidinediones (TZDs) which act as high-affinity agonists of the nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARγ), is clinically used as an antidiabetic drug which could attenuate the insulin resistance associated with obesity, hypertension, and impaired glucose tolerance in humans. However, recent studies reported that ROSI had significant anticancer effects on various human malignant tumor cells. Mounting evidence indicated that ROSI could exert anticancer effects through PPARγ-dependent or PPARγ-independent ways. In this review, we summarized the PPARγ-dependent antitumor activities of ROSI, which included apoptosis induction, inhibition of cell proliferation and cancer metastasis, reversion of multidrug resistance, reduction of immune suppression, autophagy induction, and antiangiogenesis; and the PPARγ-independent antitumor activities of ROSI, which included inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, inhibition of prostaglandin E2 (PGE2), increasing MAPK phosphatase 1 (MKP-1) expression and regulation of other apoptosis-related cell factors. In addition, we discussed the anti-cancer application of ROSI by monotherapy or combination therapy with present chemotherapeutic drugs in vitro and in vivo. Moreover, we reviewed the phase I cancer clinical trials related to ROSI combined with chemotherapeutics and phase II trials about the anti-cancer effects of ROSI monotherapy and the radiotherapy sensitivity of ROSI.