Antiproliferative effects of a new bis-indolinone on ovarian cancer Cells

Knoevenagel adducts exhibiting two indole nuclei linked to an aromatic core have allowed the identification of derivatives endowed with interesting antiproliferative activity profiles. We focused our study on the effect of a new bis-indolinone compound on the ovarian cancer cell line (IGROV1). Our compound showed remarkable selectivity against IGROV1, without affecting healthy human fibroblast cells. The technique of quantitative phase imaging of live cells was performed to investigate the effects on cell proliferation, cell morphology and motility. Moreover, to elucidate the antitumor mechanism of action of the new bis-indolinone compound, we studied its effect on the modulation of histone acetylation and genes expression. We focused on the expression of cyclin D1 and RAD51, involved in DNA repair process. Our results showed that this compound causes proliferation arrest. The antiproliferative effect is characterized by a growth arrest in the G0/G1 phase, leading to a decrease in the population in S and G2/M. The treatment induces a reduction in motility, in particular decreases individual cell displacement and velocity at a higher rate in IGROV1 compared to normal fibroblast cells. Epigenetic analysis showed histone hyperacetylation, leading to downregulation of cyclin D1 and a5 subunit of integrin b1 gene transcription. It’s known that cyclin D1 downregulation increases cell sensitivity to radiation in vitro and in vivo reducing RAD51 recruitment to damaged DNA. Furthermore, we have shown that 24 hours treatment with our compound increases radiosensitivity by causing greater DNA damage, similar to DNA damage induced by cyclin D1 gene silencing. This new bis-indolinone compound is a promising anticancer tool that could be used in association with chemo- and radiation-therapy.