Anticancer activity of the protein kinase C modulator HMI‐1a3 in 2D and 3D cell culture models of androgen‐responsive and androgen‐unresponsive prostate cancer. Issue 5 (17th April 2018)

• Record Type: Journal Article
• Authors: Jäntti, Maria H.; Talman, Virpi; Räsänen, Kati; Tarvainen, Ilari; Koistinen, Hannu; Tuominen, Raimo K.
• Is Part Of: FEBS open bio. Volume 8:Issue 5(2018)
• Page Start: 817
• Page End: 828
• Publication Date: 2018-04-17
• Subjects: drug development -- prostate cancer -- protein kinase C -- senescence; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.12419
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : Prostate cancer is one of the most common cancers in men. Although it has a relatively high 5‐year survival rate, development of resistance to standard androgen‐deprivation therapy is a significant clinical problem. Therefore, novel therapeutic strategies are urgently needed. The protein kinase C (PKC) family is a putative prostate cancer drug target, but so far no PKC‐targeting drugs are available for clinical use. By contrast to the standard approach of developing PKC inhibitors, we have developed isophthalate derivatives as PKC agonists. In this study, we have characterized the effects of the most potent isophthalate, 5‐(hydroxymethyl)isophthalate 1a3 (HMI‐1a3), on three prostate cancer cell lines (LNCaP, DU145, and PC3) using both 2D and 3D cell culture models. In 2D cell culture, HMI‐1a3 reduced cell viability or proliferation in all cell lines as determined by the metabolic activity of the cells (3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyl‐tetrazolium bromide assay) and thymidine incorporation. However, the mechanism of action in LNCaP cells was different to that in DU145 or PC3 cells. In LNCaP cells, HMI‐1a3 induced a PKC‐dependent activation of caspase 3/7, indicating an apoptotic response, whereas in DU145 and PC3 cells, it induced senescence, which was independent of PKC. This was observed as typical senescent morphology, increased β‐galactosidase activity, and upregulation of the senescence marker p21 and downregulation of E2F transcription factor 1. Using a multicellular spheroid model, we further showed that HMI‐1a3 affects the growth of LNCaP and DU145 cells in a 3D culture, emphasizing its potential as a lead compound for cancer drug development. Abstract : In prostate cancer, the development of resistance to current treatments is a prevalent problem, and new therapeutic strategies are therefore urgently needed. Here, we demonstrate anticancer activity of the protein kinase C activator 5‐(hydroxymethyl)isophthalate 1a3 (HMI‐1a3) using three prostate cancer cell lines. HMI‐1a3 reduced cell viability by either inducing apoptosis or cellular senescence. Importantly, the latter was observed in aggressive androgen‐irresponsive prostate cancer cells.