Repurposing Phenylbutyrate: versatile anticancer agent

Phenylbutyrate (PB), a short-chain fatty acid derivative, is primarily recognized as an ammonia scavenger and histone deacetylase inhibitor (HDACi). Initially developed for managing urea cycle disorders, PB has recently gained attention for its anticancer properties. Through its HDAC inhibition, PB can influence gene expression, promoting cell cycle arrest, apoptosis, and differentiation in various cancer cell lines. Beyond its epigenetic effects, PB inhibits critical metabolic enzymes, disrupts cancer cell metabolism, and reduces tumor invasiveness by limiting epithelial–mesenchymal transition (EMT). These multifunctional properties make PB a promising candidate for cancer therapy, either as a standalone agent or combined with conventional treatments, offering new avenues for enhancing therapeutic efficacy against various malignancies.

Histone Deacetylase Inhibition (HDACi)

Phenylbutyrate acts as a histone deacetylase inhibitor, altering gene expression by modifying chromatin structure. This mechanism promotes apoptosis and cell cycle arrest, with studies showing enhanced cytotoxicity in combination with conventional chemotherapy agents in colorectal cancer models. In prostate and multiple myeloma cell lines, phenylbutyrate downregulated anti-apoptotic proteins, such as Bcl-XL, and promoted the pro-apoptotic caspase cascade.

Inhibition of Epithelial–Mesenchymal Transition (EMT)

In oral squamous cell carcinoma (OSCC), phenylbutyrate inhibited EMT by downregulating the transforming growth factor-β (TGF-β) pathway and decreasing mesenchymal markers. This mechanism prevented migration and invasion of OSCC cells, demonstrating significant antitumor effects in vitro and in vivo.

PDK Inhibition and Metabolic Regulation

Phenylbutyrate was found to inhibit specific pyruvate dehydrogenase kinase (PDK) isoforms, especially PDK2 and PDK3, enhancing the pyruvate dehydrogenase complex (PDH) activity. This effect promotes cellular energy production via the tricarboxylic acid (TCA) cycle, potentially disrupting the Warburg effect.

Cell Cycle Arrest and Induction of Differentiation

In glioblastoma and other cancer cell lines, phenylbutyrate induced cell cycle arrest, specifically by upregulating the cell cycle inhibitor p21. Additionally, its differentiation-inducing properties helped reduce the aggressiveness of glioma cells and limit their proliferative potential​.

Apoptosis and Anti-Angiogenesis

Phenylbutyrate enhances apoptosis by downregulating angiogenesis-related factors like vascular endothelial growth factor (VEGF) and caveolin-1. In prostate cancer, it was shown to sensitize cells to radiation therapy, indicating potential synergy with other treatments to inhibit tumor progression.​

Key Mechanisms of Activity