Tasquinimod promotes the sensitivity of ovarian cancer cells to cisplatin by down-regulating the HDAC4/p21 pathway

To investigate the potential of Tasquinimod to influence cisplatin resistance in drug-resistant ovarian cancer cell lines through the regulation of histone deacetylase 4, known as HDAC4, or p21, we examined its effects on the cell cycle and related mechanisms. We employed reverse transcription-polymerase chain reaction, abbreviated as RT-PCR, and Western blot analyses, flow cytometry, the Cell Counting Kit-8 assay, and immunofluorescence to investigate the effects of Tasquinimod on gene expression, the cell cycle, apoptosis, cell viability, and protein levels in ovarian cancer cells. Our results demonstrated that Tasquinimod inhibited cell viability and promoted apoptosis in SKOV3/DDP and A2780/DDP cells, which are resistant to cisplatin, more effectively than cisplatin alone. When combined with cisplatin, Tasquinimod further enhanced cell apoptosis and reduced cell viability in these cell lines. Notably, this effect could be reversed by the overexpression of HDAC4.

Treatment with Tasquinimod led to the downregulation of HDAC4, B-cell lymphoma 2, known as Bcl-2, cyclin D1, and cyclin-dependent kinase 4, or CDK4 expression in SKOV3/DDP and A2780/DDP cells. Conversely, Tasquinimod treatment upregulated the expression of cleaved-Caspase-3 and p21 in these same cell lines. Furthermore, Tasquinimod inhibited cisplatin resistance in the ovarian cancer cell lines resistant to cisplatin. These effects observed in vitro were similarly observed in ovarian cancer mouse models treated with Tasquinimod.

In conclusion, our findings suggest that Tasquinimod can improve the sensitivity of ovarian cancer cells to cisplatin by downregulating the HDAC4/p21 axis. This study offers insights into potential strategies for overcoming cisplatin resistance in ovarian cancer.