Silvestrol inhibits nasopharyngeal carcinoma cells and synergizes with CX-5461: Insights from a proteomics study.

Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial cells of the nasopharynx, which is rare in Western countries but extremely prevalent in Borneo and the Southern China region. Present-day hurdles in NPC treatment that lead to poor quality of life and poor survival include distant metastasis and resistance to chemoradiotherapy. Silvestrol and its 5'''-epimer, episilvestrol, are compounds isolated from the plant Aglaia stellatopilosa, which is endemic to Borneo. Silvestrol, a protein synthesis inhibitor, preferentially inhibits the translation of cancer-associated mRNAs. CX-5461 is an inhibitor of RNA polymerase I that catalyzes rRNA synthesis. The present study sought to evaluate the potential of silvestrol as a new therapeutic for NPC with two authenticated NPC cell lines, C666-1 and HK1, and patient-derived xenografts. Concentration-response profiles were generated for silvestrol, episilvestrol, or CX-5461 as a single agent or in combination. Cell death and cell cycle progression studies were performed, followed by proteomics profiling. The findings of the present study showed that silvestrol and episilvestrol, in the nM range, inhibited NPC cells and patient-derived xenografts. While CX-5461 alone induced S and G(2)/M phase arrest in NPC cells, silvestrol or episilvestrol synergized with CX-5461 to arrest NPC cells at G(0)/G(1) and increase NPC cell death. Differential protein expression profiling revealed that silvestrol-CX-5461 combination principally targeted processes critical to protein synthesis and downregulated proteins commonly upregulated in NPC, including eukaryotic initiation factor 5A (eIF5A), c-myc, and Cyclin D1. Combining a translation inhibitor with an rRNA synthesis inhibitor may synergize to prevent the synthesis of proteins that NPC cells depend on for growth and survival. Given that c-myc, Cyclin D1 and eIF5A are essential in cell cycle progression and cell proliferation, this finding puts forward a promising new synergistic treatment approach for NPC.