Abstract
As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis.
Highlights
Histone deacetylase inhibitors (HDACIs) were expected to be effective for cancer treatment because they exhibited a variety of antitumor effects, such as cell cycle arrest, promotion of differentiation, and induction of cell death [1,2,3]
We analyzed whether the deprivation of glutamine affects reactive oxygen species (ROS) accumulation in cells treated with vorinostat at 1.6 μM, which is close to IC50 values determined after 72 h exposure in both MDA-MB-231 and human colon cancer HCT116 cells (Supplementary Figure S1A), and Cmax values (1.2 ± 0.62 μM)
Glutamine deprivation led to the reduction of the intracellular GSH level, which increased sensitivity to vorinostat with ROS accumulation
Summary
Histone deacetylase inhibitors (HDACIs) were expected to be effective for cancer treatment because they exhibited a variety of antitumor effects, such as cell cycle arrest, promotion of differentiation, and induction of cell death [1,2,3]. HDACI-resistant cells had increased levels of intracellular glutathione (GSH), which is the most abundant antioxidant [17]. XCT inhibition was suggested as a potential therapeutic strategy for cancer due to the depletion of GSH and induction of ferroptosis, which is an ironand ROS-dependent form of regulated cell death [20,21,22,23]. Our study demonstrated a previously unknown mechanism of vorinostat sensitivity that is involved in xCT expression, in addition to suggesting the feasible combination of xCT inhibitors with vorinostat to improve its efficacy in anticancer treatment
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
