Abstract 4900: Cysteamine suppresses tumor metastasis by inhibiting activity of matrix metalloproteases without inducing toxicity in mouse models of human ovarian cancer

Abstract

Abstract Previously, we demonstrated that cysteamine, a small molecule inhibitor of matrixmetalloproteases (MMPs), inhibited tumor invasion in vitro and metastasis in vivo in mouse models of human pancreatic and ovarian cancer. We have also shown that subcutaneous cysteamine administration improved the survival of mice with orthotopically transplanted pancreatic tumors. Herein, we examined the effect of cysteamine on total MMP activity, MMP isoforms and activity by substrate gel zymography in tumors obtained from orthotopic mouse model of human ovarian cancer. We also investigated any gastro-intestinal and general toxicity in vital organs of mice treated with the highest dose of cysteamine (250 mg/kg). We developed orthotopic tumors by injecting two human ovarian cancer cell lines in the ovary of female athymic nude mice. After 4 days of tumor implant, the mice were treated with different doses of cysteamine and followed for 5 weeks. Total MMP activity by fluorogenic substrate, MMP-2, 9 and 14 by ELISA and MMP activity by substrate gel zymography were measured in tumor lysates and compared with untreated tumors. We performed H&E staining in vital organs such as heart, lung, liver, kidney, spleen and brain for evaluating general toxicity of cysteamine. In addition, we examined stomach and duodenum from cysteamine treated and vehicle treated mice if they developed any ulcerations. In two orthotopic murine models of human ovarian cancer, consistent with our previous observations, tumor metastasis was significantly decreased compared to controls in cysteamine treated mice. Similarly, total MMP activity was also significantly decreased in primary tumors treated with cysteamine in a dose dependent manner (P≤0.05). Zymographic MMP activity was also decreased significantly in cysteamine treated tumors compared to control corroborating with total MMP activity (P≤0.05). Interestingly, ELISA did not show any changes in MMP expression in cysteamine treated and untreated tumors. Furthermore, we did not observe any symptoms of general toxicity in animals treated at the highest dose of cysteamine and major vital organs and gastro-intestinal organs from treated animals showed no evidence of histological changes as evident by H&E staining. In conclusion, our results suggest that cysteamine is a potent inhibitor of MMP activity without affecting expression. Cysteamine does not cause any gastro-intestinal or vital organ toxicity and may be useful therapeutic agent for ovarian cancer either alone or in combination therapy with known anti-cancer agents. Citation Format: Akiko Suzuki, Rukmini Bhardwaj, Pamela Leland, Bharat H. Joshi, Raj K. Puri. Cysteamine suppresses tumor metastasis by inhibiting activity of matrix metalloproteases without inducing toxicity in mouse models of human ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4900. doi:10.1158/1538-7445.AM2017-4900