Abstract
The isoquinolinamine FX-9 is a novel potential chemotherapeutic agent showing antiproliferative effects against hematologic and prostate cancer cell lines such as B- and T-acute lymphoblastic leukemia and prostate cancer (PC) of different species. Interestingly, FX-9 shows no hemolytic activity and low toxicity in benign adherent cells. The detailed FX-9 molecular mode of action is currently not fully understood. But application on neoplastic cells induces pro-apoptotic and antimitotic effects. Canine prostate cancer (cPC) represents a unique spontaneous occurring animal model for human androgen-independent PC. Human androgen-independent PC as well as cPC are currently not satisfactorily treatable with chemotherapeutic protocols. Accordingly, the evaluation of novel agent combinations bears significant potential for identifying novel treatment strategies. In this study, we combined FX-9 with the currently approved therapeutic agents doxorubicin, carboplatin, the demethylating substance azacitidine as well as further potentially antitumorigenic agents such as dichloroacetic acid (DCA) in order to evaluate the respective synergistic potential. The combinations with 1–5 μM FX-9 were evaluated regarding the effect after 72 hours on cell viability, cell count and apoptotic/necrotic cells in two human prostate cancer cell lines (LNCaP, PC-3) and a canine prostate cancer cell line (Adcarc1258) representing androgen-dependent and -independent PC/cPC forms. FX-9 in combination with azacitidine decreases cell viability and increases cell death with positive Bliss values. Furthermore, this decreases the cell count with neutral Bliss values on PC-3. Carboplatin in combination with FX-9 reduces cell viability with a neutral Bliss value and increases cell death on LNCaP with calculated positive Bliss values. DCA or doxorubicin in combination with FX-9 do not show synergistic or additive effects on the cell viability. Based on these results, azacitidine or carboplatin in combination with FX-9 offers synergistic/additive efficacy against prostate adenocarcinoma cell lines in vitro. The beneficial effects of both combinations are worth further investigation.
Highlights
FX-9 (3-(p-Tolyl)isoquinolin-1-amine) is a synthesized amino-substituted isoquinoline [1]
Compared to the single applications of FX-9, 1–3 μM (PC-3)/1-2 μM (LNCaP)/1 μM (Adcarc1258) FX-9 with azacitidine resulted in a reduction in cell viability
All tested FX-9 concentrations with Dichloroacetic acid (DCA) reduced cell viability in LNCaP and Adcarc1258 compared to the DMSO control, whereas in prostate cancer (PC)-3, the reduction started at 3 μM FX-9
Summary
FX-9 (3-(p-Tolyl)isoquinolin-1-amine) is a synthesized amino-substituted isoquinoline [1]. FX-9 was combined with four agents with different acting mechanisms Three of these chemotherapeutic agents were approved by the U.S Food and Drug Administration (FDA) for the treatment of human cancers: Azacitidine [11], doxorubicin [12] and carboplatin [13]. Carboplatin, a platinum-based drug, binds to DNA, thereby inhibiting replication and transcription and inducing cell death [20] It is used in the treatment of solid tumors, for example in humans with ovarian cancer [21] and in dogs with osteosarcomas [22]. DCA is not yet in clinical use, but there is a growing body of literature supporting the efficacy of DCA against cancer [24] It is not approved by the FDA and not used in the treatment of prostate cancer
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