Abstract 4581: Combination treatment of orexin-A and NAB-paclitaxel in pancreas cancer: in vitro and in vivo studies

Abstract

Abstract Orexin-A (OxA) and orexin-B (OxB) are hypothalamic peptides involved in the sleep/wake control which interact with two class A GPCR, OX1R and OX2R. We have demonstrated that OX1R was highly expressed in digestive cancers including cancer of colon1, pancreas2 and liver. In these cancers, orexin-A induces a mitochondrial apoptosis and a strong inhibition of tumor growth in nude mice xenografted with digestive cancer cell lines1,2. In the present work, we have compared and combined the effect of OxA and NAB-paclitaxel which represents the “gold standard” reference in the chemotherapeutic treatment of pancreas cancer, on their anti-tumoral properties. The incubation of AsPC-1 pancreatic cancer cell line which expressed OX1R, with 0.1μM OxA or 0.1 μM NAB-paclitaxel reveals a cell growth inhibition of 36% and 51%, respectively. The addition of 0.1 μM OxA and 0.1μM NAB-paclitaxel on AsPC-1 cells reveals a significantly cell growth inhibition of 70% suggesting that the double treatment was more efficient than individual treatment. Moreover, the addition of 0.1μM OxA and 0.1 μM NAB-paclitaxel induces 25% of cell apoptosis determined by annexin-V labeling, as compared to single treatment with 0.1μM OxA (18%) or 0.1 μM NAB-paclitaxel (12%). Additionally, we explore the sequential treatment by OxA and NAB-paclitaxel on cell growth of AsPC-1 cells. Our results evidenced than 48h treatment by OxA followed by 48h treatment of NAB-paclitaxel induced an inhibition of 35% of cell growth. In contrast, the reverse treatment (48H NAB-paclitaxel followed by 48h OxA) induces an inhibition of cell growth of 60%. OxA intraperitoneal injection (2 injections/week of 1.12 μmoles/kg OxA and/or NAB-paclitaxel) in nude mice xenografted with AsPC-1 cells, shows that OxA and NAB-paclitaxel induces an inhibition of tumoral volume of 60% and 62%, respectively. Moreover, injection of OxA plus NAB-paclitaxel induces an inhibition of tumoral volume of 70%. Sequential treatments of xenografted tumors in mice with OxA and NAB-paclitaxel was investigated and revealed 72% tumor growth inhibition when mice were treated 30 days with OxA followed by 30 days with NAB-paclitaxel and 83% tumor growth inhibition when they were treated 30 days with NAB-paclitaxel followed by 30 days with OxA. These results indicate that: 1) the addition of OxA and NAB-paclitaxel improves the effect of individual treatment; 2) the sequential treatment consisting of first OxA treatment followed by NAB-paclitaxel treatment was more efficient than reverse treatment. In conclusion, OxA was close to NAB-paclitaxel treatment in term of response and suggest that combined treatment OxA/ NAB-paclitaxel represents a new promising pancreas cancer therapy 1Voisin et al., Cancer research 2011, 71:3341-51 2Speisky et al., AACR annual meeting, 2014, San Diego, USA Citation Format: Thierry Voisin, Dina Plaut, Stephanie Dayot, Maxime Bergere, Valerie Gratio, Pascal Nicole, Anne Couvelard, Alain Couvineau. Combination treatment of orexin-A and NAB-paclitaxel in pancreas cancer: in vitro and in vivo studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4581.