Rosiglitazone enhances the apoptotic effect of 5-fluorouracil in colorectal cancer cells with high-glucose-induced glutathione

Abstract

Colorectal cancer is one of the most prevalent noncommunicable diseases worldwide. 5-Fluorouracil is the mainstay of chemotherapy for colorectal cancer. Previously, we have demonstrated that high glucose diminishes the cytotoxicity of 5-fluorouracil by promoting cell cycle progression. The synergistic impact of rosiglitazone on 5-fluorouracil-induced apoptosis was further investigated in this study. Besides control cell lines (CCD-18Co), two human colonic carcinoma cell lines (HCT 116 and HT 29) were exposed to different treatments containing 5-fluorouracil, rosiglitazone or 5-fluorouracil/rosiglitazone combination under normal glucose (5.5 mM) and high-glucose (25 mM) conditions. The cellular oxidative stress level was evaluated with biomarkers of nitric oxide, advanced oxidation protein products, and reduced glutathione. The cell apoptosis was assessed using flow cytometry technique. High glucose caused the production of reduced glutathione in HCT 116 and HT 29 cells. Correspondingly, high glucose suppressed the apoptotic effect of 5-fluorouracil and rosiglitazone. As compared to 5-fluorouracil alone (2 µg/mL), addition of rosiglitazone significantly enhanced the apoptosis (increment rate of 5–20%) in a dose-dependent manner at normal glucose and high glucose levels. This study indicates that high-glucose-induced reduced glutathione confers resistance to apoptosis, but it can be overcome upon treatment of 5-fluorouracil and 5-fluorouracil/rosiglitazone combination. Rosiglitazone may be a promising antidiabetic drug to reduce the chemotherapeutic dose of 5-fluorouracil for colorectal cancer complicated with hyperglycemia.

Important players in carcinogenesis as potential targets in cancer therapy: an update

“…In turn, Lau et al demonstrated the synergistic impact of rosiglitazone on 5-fluorouracil-induced apoptosis of two colorectal cancer cell lines (HCT-116, HT-29). The effect of this combination was significantly stronger compared to 5-FU in monotherapy [178]. Another, PPARγ agonist, trioglitazone significantly suppressed the growth of human oral squamous cell carcinoma cell lines (HSC-4, Ca9-22) by inducing cell cycle arrest [179].…”

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

“…UCP2 induction also significantly improved the response to anti-PD1 immunotherapy, and a greater reduction in tumor volume in melanoma xenografts was reported when anti-PD1 was combined with rosiglitazone [ 117 ]. Rosiglitazone also improved radiosensitivity and response to 5-fluorouracil chemotherapy by inhibiting cell growth and suppressing pancreatic and colorectal cancer cells in vitro [ 177 , 178 ].…”

Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression

“…9 In colorectal cancer, HG induces chemoresistance to 5-fluorouracil by diminishing its cytotoxic effect. 10 Recent research has demonstrated that in diabetic retinopathy, a serious T2D complication, HG inhibits autophagy and diminishes the suppressed capacity of autophagy through the autophagy lysosome pathway. 11 Autophagy is a stress response responsible for clearing aggregated cytosolic proteins, damaged organelles, and invading microorganisms.…”

“…As AMP‐activated protein kinase (AMPK) acts as an energy sensor that maintains cellular metabolic homeostasis, it has attracted increased attention in various diseases, especially malignant ones 9 . In colorectal cancer, HG induces chemoresistance to 5‐fluorouracil by diminishing its cytotoxic effect 10 . Recent research has demonstrated that in diabetic retinopathy, a serious T2D complication, HG inhibits autophagy and diminishes the suppressed capacity of autophagy through the autophagy lysosome pathway 11 …”