Isoquinolinamine FX-9 Exhibits Anti-Mitotic Activity in Human and Canine Prostate Carcinoma Cell Lines

Abstract

Current therapies are insufficient for metastatic prostate cancer (PCa) in men and dogs. As human castrate-resistant PCa shares several characteristics with the canine disease, comparative evaluation of novel therapeutic agents is of considerable value for both species. Novel isoquinolinamine FX-9 exhibits antiproliferative activity in acute lymphoblastic leukemia cell lines but has not been tested yet on any solid neoplasia type. In this study, FX-9′s mediated effects were characterized on two human (PC-3, LNCaP) and two canine (CT1258, 0846) PCa cell lines, as well as benign solid tissue cells. FX-9 significantly inhibited cell viability and induced apoptosis with concentrations in the low micromolar range. Mediated effects were highly comparable between the PCa cell lines of both species, but less pronounced on non-malignant chondrocytes and fibroblasts. Interestingly, FX-9 exposure also leads to the formation and survival of enlarged multinucleated cells through mitotic slippage. Based on the results, FX-9 acts as an anti-mitotic agent with reduced cytotoxic activity in benign cells. The characterization of FX-9-induced effects on PCa cells provides a basis for in vivo studies with the potential of valuable transferable findings to the benefit of men and dogs.

Evaluation of combination protocols of the chemotherapeutic agent FX-9 with azacitidine, dichloroacetic acid, doxorubicin or carboplatin on prostate carcinoma cell lines

“…Azacitidine, DCA, doxorubicin or carboplatin were tested in concentrations achievable in plasma [ 38 – 41 ] and showed antiproliferative effects in combination with FX-9 on PC and cPC cell lines. Similar to previous results [ 8 ], FX-9 solely leads to a dose-dependent reduction in cell viability and cell count in all cell lines. In comparison to this, two of the four tested agents, azacitidine and carboplatin, led to additive or synergistic effects on cell viability in different ways.…”

“…All test agents were stored at -20°C and different concentrations were prepared directly before each experiment. The FX-9 concentrations 1 μM, 2 μM, 3 μM, 4 μM, 5 μM were in accordance with our preliminary study [ 8 ]. The concentrations of the combination partners were chosen to reduce cell viability by approximately 50% (IC50) to show possible effects of the combination with FX-9.…”

“…These cells exhibited a higher MTS-reducing activity per cell, which led to a calculated higher cell viability, although the cell number decreased [ 48 ]. FX-9 causes morphological changes, such as enlargement and polyploidy of cells [ 8 ]. This could be responsible for the different assessment efficacy in the MTS assay.…”

“…Interestingly, cytotoxicity and hemolytic activity against non-neoplastic blood cells were not observed [ 7 ]. Furthermore, we reported a pro-apoptotic and anti-mitotic effect of FX-9 on prostate cancer cells of both human and canine origin, with decreased cytotoxic activity in non-malignant chondrocytes and fibroblasts [ 8 ].…”

Effects of the Latex of Synadenium grantii Hook F. (Euphorbiaceae) on a Preclinical Model of Canine Prostate Cancer

“…Although dogs can be considered as a model, the veterinary literature is focused on comparative morphological characters, and the information on the molecular pattern of canine PC is limited (3,4). Moreover, a very limited number of studies have investigated the antitumor effect of different compounds on the preclinical models of canine PC (8,9). Thus, the evaluation of new potential drugs for preclinical models can benefit both dogs and humans.…”