The next generation antiandrogen, Apalutamide (Apa), improves both overall survival and metastasis-free survival in men with castration... Show moreThe next generation antiandrogen, Apalutamide (Apa), improves both overall survival and metastasis-free survival in men with castration-resistant prostate cancer (CRPC). In vitro and in vivo studies were performed to characterize the mechanistic effects of Apalutamide on prostate cancer cell proliferation, invasion, and migration, and the expression of genes that regulate these processes. Apalutamide inhibited the proliferation of LNCaP human prostate cancer cells in both the presence and absence of dihydrotestosterone (DHT), and also inhibited LNCaP cell migration/invasion. At the mRNA level (RT-PCR), Apalutamide down-regulated the expression of androgen receptor (AR), c-Myc, MMP-2, MMP-9, DANCR, and lncRNA, and up-regulated TIMP-2 expression. Similar data were obtained for protein expression (western blot). In the in vivo study, male Hi-Myc mice received daily oral administration of Apalutamide beginning at age 8 weeks for 2 months, 3.5 months, or 5 months. Daily oral administration of Apalutamide reduced accessory sex gland weights by over 50% at all three time points, inhibited the progression of prostatic intraepithelial neoplasms (PIN) to cancer, and significantly affected the expression of genes that regulate invasion and migration. However, in vitro findings indicated that resistance to Apalutamide through the emergence of the AR splice variant 7 (AR-V7) following extended treatment is possible and may be reversed following knockdown of AR-V7 gene expression.In summary, these results suggest that while Apalutamide is an effective inhibitor of prostate cancer invasion/migration, further investigation into the mechanism of AR-V7 mediated Apalutamide-resistance and strategies to overcome resistance may be indicated to improve prostate cancer patient outcomes following extended periods of treatment. Show less
