Inhibition of Glutathione Peroxidase Mediates the Collateral Sensitivity of Multidrug-resistant Cells to Tiopronin

Abstract

Background: Tiopronin is a small molecule that selectively kills multidrug-resistant cancer cells. Results: Inhibition of glutathione peroxidase by tiopronin leads to elevated reactive oxygen species in MDR cells. Conclusion: Tiopronin mediates the killing of MDR cells by inhibition of glutathione peroxidases.Significance: Glutathione peroxidase inhibition may be a viable strategy for modulation of multidrug resistance in cancer.

Lower antioxidative capacity of multidrug-resistant cancer cells confers collateral sensitivity to protoflavone derivatives

“…Lorendeau et al [32] have recently published a comprehensive study on "classical" (i.e., not proto-) flavonoids' ability to selectively kill ABCC1 (MRP1)-transfected cancer cells through GSH depletion; potential use of protoflavones against such MDR cells might also be hypothesized. In addition to the role of oxidative stress in CS connected to the above-mentioned efflux transporters, Hall et al [1] demonstrated that, in P-gp overexpressing MDR cells obtained via adaptation, CS activity of the thiol-containing prescription drug tiopronin was mediated by ROS generation and the inhibition of glutathione peroxidase (GPx).…”

“…The impacts surgical intervention and/or radiotherapy. The capacity of cancer cells to develop resistance to chemotherapeutics is a significant challenge for new treatment strategies [1]. There is a wide range of cellular alterations acquired during the development of MDR: (1) overexpression of membrane efflux transporters belonging to the ATP-binding cassette family (e.g., the P-gp transporter, also known as P-glycoprotein or P-gp, which is the most prevalent among these so-called efflux pumps [2]), (2) extensively up-regulated DNA damage repair mechanisms, (3) impaired death signaling, (4) enhanced drug detoxification (e.g., up-regulation of glutathione-S-transferase enzymes), (5) lysosomal changes, (6) modification of drug molecular targets [3].…”

Modulation of ferroptosis sensitivity by TXNRD1 in pancreatic cancer cells

“…Indeed, previous reports detail increased GPX4 protein levels in the setting of genetic TXNRD1 perturbation. 33,34 To investigate this hypothesis, we assessed GPX4 protein levels in TXNRD1 -/cells through western blot, and confirmed higher GPX4 protein expression in these cells compared to WT ( Figure 3A). We also validated the ability of increased GPX4 protein levels to prevent ferroptotic cell death ( Figures 3B, S6, and S7).…”

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…MDR cell lines expressing P-gp was explained by the inhibition of glutathionperoxidase (GPx) [73,74]. Another example is the natural product Austocystin D, which possesses increased toxicity against some MDR cell lines as a result of increased activation by cytochrome P450 [75].…”