PDA Indolylmaleimides Induce Anti-Tumor Effects in Prostate Carcinoma Cell Lines through Mitotic Death

Introduction: Castrate resistant prostate cancer in men shares several characteristics with late-stage canine prostate cancer. Consequently, dogs became a model organism for the study of the human disease. Due to current insufficient therapies, evaluation of novel therapeutic agents for late-stage prostate cancer is of considerable interest for both species. Methods: In this interdisciplinary study we characterized the influence of two indolylmaleimides (PDA-66 and PDA-377) on human and canine prostate carcinoma cell lines. For this purpose, we analyzed morphology, proliferation and apoptosis, recorded live cell imaging movies and performed whole transcriptome sequencing. Results: While PDA-377 showed only weak growth inhibition on the human prostate cancer cell lines, PDA-66 inhibited proliferation and induced apoptosis in all prostate carcinoma cell lines with concentrations in the low micromolar range. Morphological characterization and whole transcriptome sequencing revealed that PDA-66 induces mitotic death through its microtubule-depolymerizing ability. Discussion: PDA-66 appears to be a worthwhile anti-mitotic agent for further evaluation. The similarities in cellular and molecular response observed in the cell lines of both origins form a solid basis for the use of canine PCa in vivo models to provide valuable transferable findings to the benefit of both species. Examination of the mediated effects by PDA-66 application on human and canine prostate carcinoma cell lines