UCN-01, a Protein Kinase C Inhibitor, Inhibits Endothelial Cell Proliferation and Angiogenic Hypoxic Response

Abstract

Angiogenesis is required for tumor formation and growth; inhibition of angiogenesis is a promising new approach in cancer therapy. UCN-01, a protein kinase C (PKC) inhibitor, induces growth arrest and apoptosis in cancer cells and was recently introduced in a phase I clinical trial. We demonstrate that UCN-01, at concentrations lower than those necessary to inhibit cancer cell growth, inhibit proliferation of human endothelial cells in vitro. Moreover, UCN-01, at concentrations as low as 32 nM, prevent microvessel outgrowth from explant cultures of rat aortic rings. Since hypoxia activates hypoxia-inducible factor (HIF-1)-dependent transcription in cancer cells that, in a paracrine fashion, drive tumor angiogenesis, we investigated the effects of UCN-01 on HIF-1-responsive promoter constructs. We report that, in addition to direct inhibitory effects on endothelial cell growth, UCN-01 abrogates hypoxia-mediated transactivation of HIF-1-responsive promoters in a prostate cancer cell line. We conclude that UCN-01, at clinically relevant concentrations, exerts an anti-neovascularization effect by blocking two important steps in vessel formation: (1) the response of cancer cells to hypoxia, and (2) endothelial cell proliferation.

The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-xL protein

“…It is therefore likely that the cytostatic effect of UCN-01 in carcinomas with constitutively activated STAT3, for example, head and neck tumours (Patel et al, 2002) might be partly due to the inhibition of STAT3 phosphorylation and the resulting Bcl-x L suppression. Furthermore, the observed antiangiogenic effect of UCN-01 (Kruger et al, 1998) may also be due to the inhibition of STAT3, which was shown to mediate angiogenesis (Wei et al, 2003). In the investigated colon cancer cell lines, however, we detected neither constitutive STAT3 Tyr705 phosphorylation nor the regulation of Bcl-x L by IL-6-activated STAT3.…”

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

“…In comparison, in normal prostate epithelial cells and endothelial cells, IC50 of UCN-01 as low as 25-35 nM. 57,58 Like normal prostate cells, normal mammary epithelial cells are very sensitive to UCN-01 with an IC50 of 10 nM. UCN-01 inhibits proliferation of endothelial cells at lower concentrations than those that inhibit prostate cancer cells.…”

“…UCN-01 inhibits proliferation of endothelial cells at lower concentrations than those that inhibit prostate cancer cells. 58 Rb is essential for UCN-01-mediated G 1 arrest in normal cells. 59 Rb status is also a determinant of response to high concentrations of UCN-01 in non-small cell lung carcinoma.…”

Cell death beyond apoptosis

“…84,95 Experimental therapeutics, such as flavopiridol and UCN-01, induce apoptosis in leukemia cells, 96,98 whereas some cancer cell lines including PC3 prostate cancer cell line are resistant. 84,[99][100][101] Nevertheless, flavopiridol induces DNA fragmentation in squamous cell carcinomas resistant to DNAdamaging drugs. 102 Inhibitors of the proteasome induce apoptosis [103][104][105] even in PC-3 cell line.…”