Photodynamic therapy (PDT) is a minimally invasive clinical procedure that selectively induces cytotoxicity in malignant cells while minimizing damage to healthy tissues. Inspired by Babu and Krishnan [1] review on PDT’s effectiveness in oral cancer treatment, we explored LXD191, a novel therapeutic agent combining lipophilic diarylacetylene and hydroxamic acid (HA), for its dual-action mechanism of PDT and histone deacetylase (HDAC) inhibition [2,3,4]. HDAC inhibitors (HDACi) are emerging as promising anticancer agents due to their ability to restore histone acetylation, often reduced in oral squamous cell carcinoma. LXD191 uniquely integrates HDAC inhibition with photosensitization, generating reactive oxygen species (ROS) under light exposure to promote selective cell death while modulating cancer-related gene expression [5]. The hydroxamic acid moiety serves as a highly effective zinc-binding group (ZBG), critical for targeting HDAC active sites and enhancing inhibition potency [6]. PDT enhances drug uptake by increasing plasma membrane permeability through photodamage, complementing LXD191’s mechanism. Preclinical studies demonstrated efficient permeation of LXD191 into oral tissues, suppression of HDAC activity, and light-triggered apoptosis in SCC-4 cells [7]. Its targeted nature ensures selective accumulation in cancer cells, sparing normal host tissues. Additionally, LXD191 modulates immune responses by influencing cytokine and chemokine profiles, including tumor necrosis factor (TNF-α), amplifying apoptosis. Combining HDAC inhibition with TNF-α-related apoptosis-inducing ligands further enhances its anticancer efficacy. Mechanistically, LXD191 disrupts HDAC-histone H3 interactions, promoting histone H3 acetylation and reactivating tumor-suppressor gene expression. ROS generation by PDT triggers direct photokilling and indirect cell death through zinc chelation, inhibiting histone deacetylation. Cellular localization studies confirmed LXD191’s accumulation in lipid-rich organelles, low toxicity, and capability to induce apoptosis via procaspase-3 activation and caspase-3 conversion. In conclusion, LXD191 offers a groundbreaking dual-action therapy for oral cancer by combining HDAC inhibition and PDT. Its preclinical success in reducing tumor growth with minimal side effects highlights its potential for clinical translation, warranting further trials to validate safety and efficacy (Fig. 1).

Schematic representation of dual action mechanism of photodyanamic therapy for oral cancer treatment.