PX‐12 synergistically enhances the therapeutic efficacy of vorinostat under hypoxic tumor microenvironment in oral squamous cell carcinoma in vitro

Abstract

AbstractHypoxia 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.