Hypoxia is a characteristic feature of solid tumors, including oral squamous cell carcinoma (OSCC), which causes therapeutic resistance. The hypoxia‐inducible factor 1‐alpha (HIF‐1α) is a key regulator of hypoxic tumor microenvironment (TME) and a promising therapeutic target against solid tumors. Among other HIF‐1α inhibitors, vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) targeting the stability of HIF‐1α, and PX‐12 (1‐methylpropyl 2‐imidazolyl disulfide) is a thioredoxin‐1 (Trx‐1) inhibitor preventing accumulation of HIF‐1α. HDACis are effective against cancers; however, they are accompanied by several side effects along with an emerging resistance against it. This can be overcome by using HDACi in a combination regimen with Trx‐1 inhibitor, as their inhibitory mechanisms are interconnected. HDACis inhibit Trx‐1, leading to an increase in the production of reactive oxygen species (ROS) and inducing apoptosis in cancer cells; thus, the efficacy of HDACi can be elevated by using a Trx‐1 inhibitor. In this study, we have tested the EC50 (half maximal effective concentration) doses of vorinostat and PX‐12 on CAL‐27 (an OSCC cell line) under both normoxic and hypoxic conditions. The combined EC50 dose of vorinostat and PX‐12 is significantly reduced under hypoxia, and the interaction of PX‐12 with vorinostat was evaluated by combination index (CI). An additive interaction between vorinostat and PX‐12 was observed in normoxia, while a synergistic interaction was observed under hypoxia. This study provides the first evidence for vorinostat and PX‐12 synergism under hypoxic TME, at the same time highlighting the therapeutically effective combination of vorinostat and PX‐12 against OSCC in vitro.
Hypoxia and acidosis are ubiquitous hallmarks of the tumor microenvironment (TME), and in most solid cancers they have been linked to rewired cancer cell metabolism. These TME stresses are linked to changes in histone post-translational modifications (PTMs) such as methylation and acetylation, which lead to tumorigenesis and drug resistance. Hypoxic and acidotic TME cause changes in histone PTMs by impacting the activities of histone-modifying enzymes. These alterations are yet to be extensively explored in oral squamous cell carcinoma (OSCC), one of the most prevalent cancers in developing countries. Hypoxic, acidotic, and hypoxia with acidotic TME affecting histone acetylation and methylation in the CAL27 OSCC cell line was studied using LC-MS-based proteomics. The study identified several wellknown histone marks, in the context of their functionality in gene regulation, such as H2AK9Ac, H3K36me3, and H4K16Ac. The results provide insights into the histone acetylation and methylation associated with hypoxic and acidotic TME, causing changes in their level in a position-dependent manner in the OSCC cell line. Hypoxia and acidosis, separately and in combination, cause differential impacts on histone methylation and acetylation in OSCC. The work will help uncover tumor cell adaptation to these stress stimuli in connection with histone crosstalk events.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.