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
Autor: | Maria Jäntti, Raimo K. Tuominen, Hannu Koistinen, Ilari Tarvainen, Kati Räsänen, Virpi Talman |
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Přispěvatelé: | Faculty of Pharmacy, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Medicum, Department of Clinical Chemistry and Hematology, Clinicum, Drug Research Program, Regenerative pharmacology group, PREP in neurodegenerative disorders, HUS Abdominal Center, HUSLAB |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
EXPRESSION senescence INHIBITION PACLITAXEL urologic and male genital diseases General Biochemistry Genetics and Molecular Biology ACTIVATION PATHWAY 03 medical and health sciences Prostate cancer 0302 clinical medicine Downregulation and upregulation DU145 DOMAIN LNCaP medicine Viability assay ESTER-INDUCED APOPTOSIS Protein kinase C Research Articles Chemistry medicine.disease prostate cancer drug development 3. Good health 030104 developmental biology PKC-DELTA 12-O-TETRADECANOYLPHORBOL-13-ACETATE-INDUCED APOPTOSIS Apoptosis Cell culture 317 Pharmacy 030220 oncology & carcinogenesis Cancer research 1182 Biochemistry cell and molecular biology Research Article protein kinase C |
Zdroj: | FEBS Open Bio |
Popis: | 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. |
Databáze: | OpenAIRE |
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