A 5-Nitrobenzoate-Derived Compound Elicits Anti-Cancer Metastatic Activity By Inhibition Of Poloplanin-Stimulated Tumor Cell-Induced Platelet Aggregation

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PATumor cells dissemination and survival within the vascular system play an important role in cancer metastasis and is a clinical challenge for post-surgical cancer management. Podoplanin (PDPN) is one of the frequently over-expressed proteins in squamous cell carcinoma. By binding to platelet C-type lectin-like receptor 2 (CLEC-2), PDPN stimulates tumor cell-induced platelet aggregation (TCIPA) and facilitates cancer cell metastasis. In this study, a series of 5-nitrobenzoate-derived compounds were synthesized to screen for anti-cancer metastasis compounds that elicit functional blockage of PDPN-stimulated CLEC-2 activation and TCIPA. Platelet aggregation assays indicate that the small molecule compound 2CP selectively inhibited PDPN-induced platelet aggregation and the TCIPA of C6/Lung and osteosarcoma cells which expressed high levels of PDPN protein. Mouse tail bleeding time assay revealed that 2CP did not cause deleterious effects on normal blood hemostasis. In xenograft experimental metastasis model, 2CP possessed in vivo anti-cancer metastatic activity and augments the therapeutic efficacy of cisplatin; both the formation of pulmonary tumor foci and the body weight loss associated with the increased tumor burden were attenuated by combined treatment of 2CP and cisplatin. In conclusion, we present a novel and non-cytotoxic small molecule compound 2CP that elicits specific inhibitory effects on tumor cells-platelet interaction through intervening PDPN/CLEC-2 interaction and PDPN-mediated TCIPA. The findings are valuable for future application of 2CP in the prevention and treatment of cancer metastasis.Citation Format: Yao-Wen Chang, Pei-Wen Hsieh, Kowit-Yu Chong, Ching-Ping Tseng. A 5-nitrobenzoate-derived compound elicits anti-cancer metastatic activity by inhibition of poloplanin-stimulated tumor cell-induced platelet aggregation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4477. doi:10.1158/1538-7445.AM2015-4477