Abstract
BackgroundIn recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model.MethodsBoth androgen-independent (LNCaP) and androgen-dependent (PC3) PCa cell lines were treated with a range of Nintedanib doses for 72 h, and effect on cell growth and expression of angiogenesis associated VEGF receptors was analyzed. In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6–10 weeks after stopping drug treatments. At the end of treatment schedule, mice were sacrificed and ventral lobe of prostate was excised along with essential metabolic organ liver, and subjected to histopathological and extensive molecular evaluations.ResultsThe total cell number decreased by 56–80% in LNCaP and 45–93% in PC3 cells after 72 h of Nintedanib treatment at 2.5–25 μM concentrations. In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. A decreased microvessel density and VEGF immunolocalization was observed, besides decreased expression of Androgen Receptor (AR), VEGFR-1 and FGFR-3 in some of the treated groups. No changes were observed in the histological liver analysis.ConclusionsNintedanib treatment was able to significantly decrease the growth of PCa cell lines and also delay growth and progression of PCa lesions to higher grades of malignancy (without inducing any hepatotoxic effects) in TRAMP mice. Furthermore, it was observed that Nintedanib intervention is more effective when administered during the early stages of neoplastic development, although the drug is capable of reducing cell proliferation even after treatment interruption.
Highlights
In recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation
Different animal models have been used in anti-prostate cancer (PCa) efficacy studies, including the transgenic adenocarcinoma for the mouse prostate (TRAMP) model, which mimics the spontaneous growth and progression of PCa as it occurs in humans
According to Wikstrom et al [5], lesions found in the prostate of the TRAMP mice can be classified into different grades histopathologically, low and high grade prostatic intraepithelial neoplasia (PIN) lesions which advance to different stages of adenocarcinoma, such as well-differentiated, and poorly differentiated adenocarcinoma; in addition there are extensive changes in the expression of molecular markers [6]
Summary
Anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model. Well-differentiated adenocarcinoma is characterized by the invasion of epithelial cells in the prostatic stroma and basement membrane disruption This latter grade lesion can develop into poorly differentiated adenocarcinoma, where the tumor is made up of a cluster of indistinct cells [7]
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