# Therapeutic Potential and Challenges of Pioglitazone in Cancer Treatment
###### Abstract  
Pioglitazone (ACTOS) is a thiazolditione for peroxisome proliferatorator-activated receptor \(\gamma\) (PPAR-\(\gamma\)) that has been well established for the second or third line treatment of type 2 diabetes mellitus. Beyond the effects on glucose metabolism, pioglitazone displays positive effects on lipid metabolism, blood pressure, endothelial function, bone density, and apoptosis of cancer cells. In fact, according to in vitro experiments and preclinical studies, PPAR-\(\gamma\) ligand is currently considered a potential target for both chemoprevention and cancer therapy. PPAR-\(\gamma\) ligands are known to inhibit cancer cell proliferation and metastasis through terminal differentiation and underexpression of inflammatory mediators. Despite its anticancer properties, pioglitazone was withdrawn by the national medicine agencies of France and Germany, due to reports of increased incidence of bladder cancer. These reports were associated with European populations undergoing higher doses and longer durations of treatment. In this review, we discuss the pharmacokinetics, therapeutic potential, and limitations regarding the clinical use of pioglitazone, with a focus on cancer treatment.  
pioglitazone; cancer; type 2 diabetes 22 November 2021  
8 February 2025  
10 February 202510 February 202  
alpha-glucosidasealge inhibitors, insulin, glucagon-like peptide-1 receptor agonist, dipeptidyl1 peptidase 4 inhibitors, sodium-glucose co-transporter 2 inhibitors, and thiazolinedines, such as pioglitazone [10]. Pioglitazone is typically administered orally, with the optimal dose customized based on clinical status. According to the European Medicines Agency (EMA) recommendations, the initial dose ranges from 15 to 45 mg once daily. The dose may be increased if inadequate glycemic control is achieved. Alternatively, it may need to be decreased if the patient is receiving pioglitazone along with other diabetes medications (insulin, chlorpropamide, gibbenclature, gliclazide, and tolbutamide). The tablets should be administered once a day with water, either with or without food. After three to six months, the patients should be evaluated and treatment discontinued if considered non-beneficial [11].  
However, despite its effectiveness in enhancing glycemic control, concerns have been raised about its safety profile, one of which regards an increased bladder cancer risk. Notably, indications of a higher incidence of bladder cancer among pioglitazone users prompted the French and German pharmaceutical regulators to withdraw the medication from the market in May 2011. Nevertheless, the medicine remained available throughout the rest of Europe [12].  
The aim of this literature review is to thoroughly evaluate pioglitazone's safety profile and efficacy, with an emphasis on its association with bladder cancer. This review summarizes clinical data, epidemiological studies, and regulatory recommendations in an effort to evaluate the risk-benefit ratio of pioglitazone. Its evaluation will shed light into current clinical practice and direct future studies to explore the multiple therapeutic applications of pioglitazone.