Effective killing of Gleevec-resistant CML cells with T315I mutation by a natural compound PEITC through redox-mediated mechanism

Abstract

Mutation of Bcr-Abl is an important mechanism by which chronic myelogenous leukemia (CML) cells become resistant to Gleevec. The T315I mutation is clinically significant since CML cells harboring this mutation are insensitive to Gleevec and other Bcr-Abl-targeted drugs. Identification of new agents capable of effectively killing CML cells with T315I mutation would have important therapeutic implications in Gleevecresistant CML. Here, we showed that b-phenylethyl isothiocyanate (PEITC), a natural compound found in vegetables, is effective in killing CML cells expressing T315I BCR-ABL. Treatment of leukemia cell lines harboring wild-type or mutant Bcr-Abl with 10 lM PEITC resulted in an elevated ROS stress and a redox-mediated degradation of the BCR-ABL protein, leading to massive death of the leukemia cells. Antioxidant NAC attenuated the PEITC-induced oxidative stress in CML cells and prevented the degradation of BCR-ABL, caspase-3 activation and cell death. We further showed that the ROS-induced degradation of BCR-ABL was mediated partially by caspase-3 and the proteasome pathway. The ability of PEITC to effectively kill T315I-positive CML cells was further confirmed using primary leukemia cells isolated from CML patients. Our results suggest that PEITC is a promising compound capable of killing Gleevec-resistant CML cells through a ROS-mediated mechanism and warrants further investigations.

Inhibition of hypoxia inducible factor by phenethyl isothiocyanate

“…Growth inhibitory effects of ITCs may involve direct conjugation and functional modification of key cell regulatory proteins and/or via increased ROS production following depletion of intracellular GSH [25,31,68]. ROS generally promote activation of HIF [41][42][43][44][45][46][47] and consistent with this, we demonstrated that NAC and catalase decreased induction of HIF activity in hypoxic conditions.…”

“…Enhancing cellular GSH levels by treatment with GSH or its metabolic precursor NAC can interfere with PEITC-induced growth inhibition [25,31,68]. Thus, we wanted to determine whether NAC also interfered with inhibition of HIF activity by PEITC.…”

Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation

“…We reason that modulating gemcitabineinduced redox regulatory mechanisms by reducing GSH pool may affect cell survival and drug sensitivity. PEITC, a novel compound that has been reported to deplete GSH and subsequently elevate oxidative stress (15,17), may circumvent such protection and enhance the antipancreatic cancer activity of gemcitabine.…”

“…b-Phenylethyl isothiocyanate (PEITC), a natural compound found in cruciferous vegetables, depletes GSH and selectively kills cancer cells while sparing healthy cells (14)(15)(16)(17). Given the fact that stimulation of ROS is generated by gemcitabine in PDAC cells, we hypothesized that the cells increase cellular GSH to prevent oxidative damage and that PEITC enhances the effect of gemcitabine-induced ROS through the redox modulation.…”

Penta-O-galloyl-beta-D-glucose enhances antitumor activity of imatinib and suppresses the growth of K562 cells in mice

“…Rakshit et al (2010) reported the role of ROS in chlorogenic acid (Chi)-induced cell death in CML cell lines as well as primary leukemia cells from CML patients. In addition, Zhang et al (2008) reported that beta-phenylethyl isothiocyanate (PEITC) exerted the cytotoxic effect in Glivec-resistant CML cells by regulating redox signaling. These evidences suggest the potential of natural products for CML treatment.…”