Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer

Abstract

The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

TNBG-5602, a novel derivative of quinoxaline, inhibits liver cancer growth via upregulating peroxisome proliferator-activated receptor γ in vitro and in vivo

“…[33][34][35] Some synthetic PPARc ligands, such as rosiglitazone, troglitazone and ciglitazone, inhibit the proliferation of tumour cells and induce tumour cell apoptosis. [36][37][38][39][40] In this study, we found that TNBG-5602 can increase the expression of PPARc at the mRNA and protein levels in vitro and in vivo. Further study found that a PPARc agonist (RSG) can enhance the lipid accumulation of TNBG-5602, while a PPARc inhibitor (T0070907) can reverse the lipid accumulation of TNBG-5602.…”

“…It was discovered that overexpression of PPARγ can inhibit cell proliferation and tumour growth, while it is reversed in PPARγ‐silenced cancer cells . Some synthetic PPARγ ligands, such as rosiglitazone, troglitazone and ciglitazone, inhibit the proliferation of tumour cells and induce tumour cell apoptosis …”

Research Advances in the Correlation between Peroxisome Proliferator-Activated Receptor-γ and Digestive Cancers

“…With stronger metabolic activity than that of the natural ligand, the synthetic ligand is widely used in diabetes management. Moreover, a growing body of research has discovered that the synthetic ligand has an antitumor effect either used independently or combined with other medications, and the mechanism underlying this is a research hotspot at present [ 13 ]. Certain nonsteroidal drugs, such as indomethacin and ibuprofen, are reported to possess an antineoplastic effect, although their metabolic activity is extremely low [ 14 ].…”

Pioglitazone Alters the Proteomes of Normal Bladder Epithelial Cells but Shows No Tumorigenic Effects

“…Currently, the U.S. Food and Drug Administration allows the use of pioglitazone in patients with special caution to those with a prior history or active BC [10]. A potential reason for this observation could be that PPARγ signaling in BC cells may provide a tumor micro-environment that allows for de novo lipogenesis of lipids that can be utilized in increasing tumor mass and energy usage [11]. However, other studies have shown that TZDs posed no risk on survival in BC patients who underwent radical cystectomy [12].…”