Abstract
Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related deaths in American men. Proliferating cells have higher need for nutrients and oxygen, triggering angiogenesis that plays a critical role in tumor growth, progression and metastasis. Consequently, immense focus has converged onto inhibitors of angiogenesis in cancer treatment, such as Nintedanib, which has shown exceptional antitumor activity via inhibiting cell proliferation and the resulting tumor growth, primarily due to its combined action on tumor cells, endothelial cells and pericytes. Accordingly, here we assessed both in vitro and in vivo efficacy of Nintedanib in PCa. The results showed that Nintedanib decreased cell viability in both androgen dependent- and -independent PCa cells, together with a decrease in cell motility and invasiveness. Nintedanib also reduced the expression of significant genes responsible for cell cycle progression. PCa PC3 xenograft-carrying nude mice treated with Nintedanib showed significantly decreased tumor volume and cell proliferation alongside diminished levels of pro-angiogenic molecules and blood vessel densities. In conclusion, we report that Nintedanib has strong efficacy against PCa in pre-clinical models via modulation of various pathways, and that it could be employed as a promising new strategy to manage PCa clinically.
Highlights
Prostate cancer (PCa) is the most common type of cancer in men; according to Siegel (2017) 161,360 new cases of the disease were estimated for 2017 within the United States alone, with approximately 26,730 resulting fatalities, making PCa the second-largest cause of cancer-associated deaths in the US males[1]
Results indicated that the PCa cells treated with 2.5 μM of Nintedanib required longer time to close the wound (Fig. 4a), demonstrating that the drug Nintedanib inhibited the migratory potential of PCa cells
Nintedanib exposure led to cell cycle arrest of PCa cells by decreasing gene expression and levels of key molecules involved in cell cycle progression, showing a completely novel mode of action of this antiangiogenic drug
Summary
Prostate cancer (PCa) is the most common type of cancer in men; according to Siegel (2017) 161,360 new cases of the disease were estimated for 2017 within the United States alone, with approximately 26,730 resulting fatalities, making PCa the second-largest cause of cancer-associated deaths in the US males[1]. Several tyrosine kinase inhibitors of angiogenesis have been shown to possess anti-tumor activity, such as sorafenib, sunitinib, erlotinib and vandetanib for the treatment of several types of cancers[10,11,12,13] These agents either fail to show improvements or prove to be excessively toxic at some point along the treatment, even when used in combination with well-established chemotherapeutic agents[14,15,16]. Major attention has been paid to novel agents such as Nintedanib (BIBF 1120), which is capable of inhibiting all three families of receptors engaged in the process of angiogenesis This angiokinase inhibitor targets VEGFR (vascular endothelial growth factor receptor) involved in both cell proliferation and migration, and PDGFR (platelet-derived growth factor receptor) and FGFR (fibroblast growth factor receptor), indirectly responsible for providing sustenance to new vessels by controlling the action of pericytes and smooth muscle cells[5,6]. We have previously reported the in vivo efficacy of Nintedanib in pre-clinical mouse models of PCa; in that background, the present study was an effort to understand the molecular mechanisms involved in Nintedanib efficacy against PCa by evaluating its effects both in vitro and in vivo in human PCa cell lines and human PCa tumor xenograft model, respectively
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