Abstract A92: Aminomethylphosphonic acid inhibits human prostate xenograft tumor growth through interfering glycine synthesis in the cancer cells

Abstract

Abstract Rapidly proliferating cancer cells consume more glycine than rapidly proliferating normal cells, which offers an opportunity to target glycine metabolism in the cancer cells while avoiding causing severe side effects in the normal cells. Two-thirds of glycine consumed is synthesized intracellularly, e.g., through conversion of serine into glycine by serine hydroxymethyltransferase (SHMT). Aminomethylphosphonic acid (AMPA, C3H3NO5P) is an analog to glycine, which inhibits SHMT enzyme activity, thus blocking conversion of serine into glycine. Our previous in-vitro studies have shown that AMPA inhibited cell growth in six cancer cell lines (including four human prostate cancer cell lines PC-3, DU-145, LNCaP, and C4-2B), while had little effects on two human normal immortalized prostatic epithelial cell lines (RWPE-1 and pRNS-1-1). The purpose of the present study was to determine if AMPA could inhibit PC-3 xenograft tumor growth in nude mice. PC-3-LacZ-luc cells (stably expressing LacZ and luciferase for staining and in-vivo imaging) were first implanted subcutaneously to form tumors. Then, the tumors were cut into 2-mm pieces and surgically implanted orthotopically in the prostates of 39 six-week-old athymic nude male mice that were castrated during the same surgery. One week later, the prostate tumor sizes were measured using D-luciferin and IVIS® Lumina XRMS imaging system (PerkinElmer, Inc.). The animals were randomized into three treatment groups: 1) saline as control (n = 14); 2) 400 mg/kg/day of AMPA (n= 10); and 3) 800 mg/kg/day of AMPA (n = 15). The treatment was administrated intraperitoneally once a day until animal death. Animal body weight measurement and in-vivo imaging were performed once every 5 to 7 days. Upon animal death, tumors were harvested and weighed. Pathologic examination, immunohistochemical staining, and Western blot analyses were performed using the tumors. We found that the tumor size rapidly increased in the control group, whereas the tumor size increased only slightly in the two AMPA-treated groups (p < 0.05). Animal survival time was significantly longer in the AMPA-treated groups than the control group (p < 0.05) and the high-dose group had slightly longer survival time than the low-dose group (p = 0.087). The average final tumor weight was significantly less in the high-dose group than the control group (p < 0.05). The levels of cellular inhibitor of apoptosis protein 1 (C-IAP1) and cyclin D1 were dramatically reduced in the tumors from the two AMPA-treated groups compared to the control group. We also observed that the two AMPA-treated groups had much less intra-abdominal metastases compared to the control group. Further in-vitro studies found that AMPA inhibited migration and invasion of PC-3 cells using Transwell assays. In conclusion, we found that AMPA inhibits human prostate xenograft tumor growth through inducing apoptosis and inhibiting cellular proliferation, which suggests that AMPA may be developed into a new treatment for prostate cancer. Citation Format: Keshab R. Parajuli, Qiuyang Zhang, Sen Liu, Zongbing You. Aminomethylphosphonic acid inhibits human prostate xenograft tumor growth through interfering glycine synthesis in the cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A92.