Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Metastatic uveal melanoma (MUM) presents a significant clinical challenge with limited effective treatments.
• Current therapeutic strategies for MUM offer minimal patient survival benefits, necessitating novel approaches.

Purpose of the Study:

• To evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), against ocular and liver metastatic uveal melanoma (MUM) cell lines.
• To elucidate the molecular mechanisms underlying the anti-cancer effects of ACY-1215, focusing on cell cycle, apoptosis, and signaling pathways.

Main Methods:

• In vitro and in vivo studies using primary ocular UM cell lines (Mel270) and a liver MUM cell line (OMM2.5).
• Assessment of cell survival, proliferation, cell cycle arrest (flow cytometry), apoptosis, and protein expression (p-ERK).
• Proteome profiling to identify affected signaling pathways, including microphthalmia-associated transcription factor (MITF), and validation with ML329.

Main Results:

• ACY-1215 demonstrated a significant, dose-dependent reduction in the survival of Mel270 and OMM2.5 cells in vitro.
• In vivo studies showed ACY-1215 attenuated OMM2.5 xenografts in zebrafish larvae.
• ACY-1215 induced S-phase cell cycle arrest and apoptosis in OMM2.5 cells, reducing p-ERK levels and impacting MITF signaling.

Conclusions:

• ACY-1215 exhibits significant anti-cancer activity against uveal melanoma cells, both in vitro and in vivo.
• The anti-cancer effects are mediated through cell cycle arrest, apoptosis induction, and modulation of the MITF signaling pathway.
• ACY-1215 and MITF inhibition with ML329 represent potential therapeutic strategies for metastatic uveal melanoma.