Abstract 5378: Actions of nanoparticulate tetraiodothyroacetic acid (Nanotetrac) on human prostate carcinoma xenograft growth, vascularity and integrin response to radiation

Abstract

Abstract Tetraiodothyroacetic acid (tetrac) covalently bound to a nanoparticle (poly[lactic-co-glycolic acid]) (= Nanotetrac) has anti-cancer and anti-angiogenic properties that are initiated exclusively at a cell surface receptor on integrin αvβ3 of cancer cells and dividing blood vessel cells. The anti-cancer activities are pro-apoptotic by multiple mechanisms, disorder gene expression in multiple cancer cell survival pathways and are radiosensitizing. The anti-angiogenic effects involve disruption of actions of VEGF, bFGF, PDGF and EGF. In the present studies, susceptibility of human prostate cancer cell xenografts to activity of Nanotetrac was determined in grafts in the nude mouse or to the chick chorioallentoic membrane (CAM) model and radiosensitivity was estimated in the CAM system. Androgen-sensitive LNCaP cell xenografts in the CAM exposed to Nanotetrac (1 μg/CAM) showed 40% decreases in tumor weight and vascular branch points and 50% reduction in hemoglobin content at 7 d (P < 0.01). LNCaP xenograft volumes in the male mouse were reduced by 50% at 5 days (P < 0.01), approximating the volume of the tumor cell implant. In vivo imaging system (IVIS) scans of orthotopic androgen-independent PC3 cell xenografts in the nude mouse showed substantial reduction in tumor size vs. control (PBS) at 7 d (50% reduction) and at 17 d (75% reduction) post-implantation. Radiation studies in PC3 cell tumors established in the CAM system demonstrated that within 1 h of exposure to 1-2 Gy radiation, there was apparently defensive activation (assumption of ‘open conformation’) of αvβ3. Receptor activation response to radiation was blocked by Nanotetrac. We have shown in other cancer cell lines that Nanotetrac inhibits repair of radiation-induced double-stranded DNA breaks and propose that, based on the current observations, this DNA repair effect is due to inhibition of radiation-caused activation of αvβ3. In summary, examined in two models and acting at the cell surface, Nanotetrac substantially reduces volume/weight and vascularity of human prostate cancer xenografts. The agent also inhibited activation of integrin αvβ3 that is induced by radiation exposure and is seen to be a component of the radioresistance response. Citation Format: Shaker A. Mousa, Sudha Thangirala, Murat Yalcin, John T. Leith, Aleck Hercbergs, Hung-Yun Lin, Heng-Yuan Tang, Mary K. Luidens, Paul J. Davis. Actions of nanoparticulate tetraiodothyroacetic acid (Nanotetrac) on human prostate carcinoma xenograft growth, vascularity and integrin response to radiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5378. doi:10.1158/1538-7445.AM2014-5378