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

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Jantti , M H , Talman , V , Räsänen , K , Tarvainen , I , Koistinen , H & Tuominen , R K 2018 , ' 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 ' , FEBS open bio , vol. 8 , no. 5 , pp. 817-828 . https://doi.org/10.1002/2211-5463.12419

Title: 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
Author: Jantti, Maria H.; Talman, Virpi; Räsänen, Kati; Tarvainen, Ilari; Koistinen, Hannu; Tuominen, Raimo K.
Other contributor: University of Helsinki, Faculty of Pharmacy
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Medicum
University of Helsinki, Faculty of Pharmacy
University of Helsinki, Department of Clinical Chemistry and Hematology
University of Helsinki, Drug Research Program










Date: 2018-05
Language: eng
Number of pages: 12
Belongs to series: FEBS open bio
ISSN: 2211-5463
DOI: https://doi.org/10.1002/2211-5463.12419
URI: http://hdl.handle.net/10138/235487
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 beta-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.
Subject: drug development
prostate cancer
protein kinase C
senescence
ESTER-INDUCED APOPTOSIS
PKC-DELTA
12-O-TETRADECANOYLPHORBOL-13-ACETATE-INDUCED APOPTOSIS
SENESCENCE
ACTIVATION
EXPRESSION
PATHWAY
DOMAIN
INHIBITION
PACLITAXEL
1182 Biochemistry, cell and molecular biology
317 Pharmacy
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