Abstract
Gonadotropin-releasing hormone-I (GnRH-I) has attracted strong attention as a hormonal therapeutic tool, particularly for androgen-dependent prostate cancer patients. However, the androgen-independency of the cancer in advanced stages has spurred researchers to look for new medical treatments. In previous reports, we developed the GnRH-II antagonist Trp-1 to inhibit proliferation and stimulate the autophagic death of various prostate cancer cells, including androgen-independent cells. We further screened many GnRH-II antagonists to identify molecules with higher efficiency. Here, we investigated the effect of SN09-2 on the growth of PC3 prostate cancer cells. SN09-2 reduced the growth of prostate cancer cells but had no effect on cells derived from other tissues. Compared with Trp-1, SN09-2 conspicuously inhibited prostate cancer cell growth, even at low concentrations. SN09-2-induced PC3 cell growth inhibition was associated with decreased membrane potential in mitochondria where the antagonist was accumulated, and increased mitochondrial and cytosolic reactive oxygen species. SN09-2 induced lactate dehydrogenase release into the media and annexin V-staining on the PC3 cell surface, suggesting that the antagonist stimulated prostate cancer cell death by activating apoptotic signaling pathways. Furthermore, cytochrome c release from mitochondria to the cytosol and caspase-3 activation occurred in a concentration- and time-dependent manner. SN09-2 also inhibited the growth of PC3 cells xenotransplanted into nude mice. These results demonstrate that SN09-2 directly induces mitochondrial dysfunction and the consequent ROS generation, leading to not only growth inhibition but also apoptosis of prostate cancer cells.
Highlights
Prostate cancer is the most common malignancy that occurs in the male reproductive system
SN09-2 induces prostate cancer cell-specific death We previously reported that a novel GnRH-II antagonist Trp-1 induced prostate cancer cell death [28]
Our previous studies revealed that the GnRH-II antagonist Trp-1 inhibited proliferation and stimulated death signaling in human prostate cancer cells through mitochondrial dysfunction and autophagy [27,28]
Summary
Prostate cancer is the most common malignancy that occurs in the male reproductive system. A common treatment for advanced prostate cancer is hormonal therapy combined with radiation therapy [4]. The main goal of hormonal therapy is to remove or decrease serum androgen, a potential growth stimulant for prostate cancer. In many cases, the initial regression of the tumors is followed by re-growth independent of androgen levels, increased aggressiveness, and high metastatic activity [5]. For this reason, the development of effective drugs for the treatment of androgenindependent prostate cancer is an urgent issue
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
