Researchers in Italy found that rigosertib (ON-01910) was effective as an antitumoral and radiosensitizing therapy in cholangiocarcinoma EGI-1 cell lines.
The research, published in the International Journal of Molecular Sciences, found that rigosertib halts the cell cycle in the G2/M phase and increases autophagy while also impairing proteasome activity, cell motility, and cell migration. Rigosertib was also found to be a more potent radiosensitizer than gemcitabine and 5-fluorouracil.
In addition to its effectiveness in the EGI-1 cell line, rigosertib was also tested in the TFK-1 cholangiocarcinoma cell line with similar results.
According to the study’s authors, “Rigosertib could be a potential therapeutic option, alone or in combination with radiations, for nonresectable patients with cholangiocarcinoma.”
The effects of rigosertib on cell viability were found to be dose-dependent, with a maximum effect found at a dose of 100 nM. Treatment was also found to be time-dependent, with decreasing cell viability at 24, 48, and 72 hours of treatment.
Rigosertib’s effects were also reversible at the 100 nM concentration, with cell regrowth occurring with media changes after 24 and 48 hours of treatment. Further, the treatment also caused changes in cell morphology and the number of nuclei present, providing evidence of mitotic failure and catastrophe and showing that treated cells were effectively halted in the G2/M phase.
Rigosertib is a non-ATP competitive multi-kinase inhibitor that primarily targets polo-like kinase 1 (PLK1). Inhibition of PLK1 affects the regulation of G2/M checkpoint proteins, spindle assembly, and centrosome maturation, resulting in cell cycle arrest, mitotic failure, and ultimately cell death. The halting of cells in the G2/M phase of the cell cycle also increases their radiosensitivity.
The efficacy of rigosertib has previously been demonstrated in several other solid tumors and hematologic malignancies in vitro. Despite its demonstrated effects on cancer cells, studies in normal human BJ fibroblast and ectocervix cells suggest that rigosertib is not toxic to normal human cells.
Malacrida A, Rigolio R, Celio L, et al. In vitro evaluation of rigosertib antitumoral and radiosensitizing effects against human cholangiocarcinoma cells. Int J Mol Sci. 2021;22(15):8230. doi:10.3390/ijms22158230