hs-1793 and Prostatic-Neoplasms

In many studies, resveratrol has been shown to have a chemopreventive effect in various types of cancer cells. However, the biological activity of resveratrol is limited by its photosensitivity and metabolic instability. This study investigated the effects of a novel analogue of resveratrol, HS-1793, on the expression of HIF-1α and vascular endothelial growth factor (VEGF) in PC-3 human prostate cancer cells. Hypoxic condition induced HIF-1α protein level in PC-3 cells in a time-dependent manner, and treatment with HS-1793 markedly decreased HIF-1α expression levels. HS-1793 also inhibited VEGF level. Mechanistically, HS-1793 inhibited HIF-1α and VEGF expression through multiple mechanisms. Firstly, HS-1793 inhibited phosphorylation of PI3K and Akt in PC-3 cells. Furthermore, HS-1793 substantially induced HIF-1α protein degradation through the proteasome pathway. Finally, HS-1793 inhibited hypoxia-induced PC-3 cell migration. These data suggest that HS-1793 may inhibit human prostate cancer progression and angiogenesis by inhibiting the expression of HIF-1α and VEGF. Moreover, HS-1793 showed more potent effects than resveratrol on the cytotoxic effects on PC-3 cells. Taken together, these results implied that HS-1793, a novel analogue of resveratrol, may be a new potent chemopreventive agent against human prostate cancer cells.

Topics: Cell Hypoxia; Cell Line, Tumor; Cell Movement; Cell Survival; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Naphthols; Neovascularization, Pathologic; Prostatic Neoplasms; Resorcinols; Signal Transduction; Vascular Endothelial Growth Factor A

Since resveratrol is not a potent cytotoxic compound when compared with other chemotherapeutic agents, several previous studies have been performed to obtain synthetic analogs of resveratrol with potent activity. Our previous study demonstrated that the resveratrol analog HS-1793 showed stronger antitumor activity than resveratrol in various cancer cells. We examined the antitumor activity exerted by HS-1793 in prostate cancer cells, and we observed that HS-1793 acts as a polyploidy inducer. Noticeably, multinucleation and polyploidization were induced in most LNCaP cells treated with HS-1793 at the dose causing a slight decline in cell viability. However, the induction of multinucleation and polyploidization was much lower in PC-3 prostate cancer cells treated with the same dose of HS-1793. Western blot and RT-PCR analyses showed that the expression of Aurora B was almost undetectable in LNCaP cells, but it was highly expressed in PC-3 cells. Further, silencing of Aurora B sensitized PC-3 cells to HS-1793-induced multi-nucleation. These results indicate that expression of Aurora B determines multinucleation in prostate cancer cells treated with HS-1793. Additional assays using multiple cancer cell lines show that the population of multinucleated cells induced by HS-1793 treatment is inversely proportional to Aurora B expression. We further elicited that the HS-1793-induced polyploid LNCaP cells are vulnerable to downregulation of Bcl-xL. Since the polyploidization in LNCaP induced by HS-1793 does not appear to cause definite commitment to apoptosis, the termination of polyploid cells by inhibition of Bcl-xL could provide an advantageous means to improve chemotherapeutic efficacy of HS-1793.

Topics: Antineoplastic Agents; Apoptosis; Aurora Kinase B; Aurora Kinases; bcl-X Protein; Cell Line, Tumor; Cell Survival; Down-Regulation; Drug Synergism; HCT116 Cells; Humans; K562 Cells; Male; Naphthols; Polyploidy; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Resorcinols; U937 Cells