Abstract 5540: Antitumor efficacy of synthetic formulations of active components in Arum palaestinum extracts in head and neck squamous cell carcinoma
Authors: Vishwakarma Vikalp , Crooker Kyle , Snyder Vusala , Straub Jeffrey , Cole Caitlin , Lee Annie , Bittel Lisa Stehno , Thomas Sufi 
Published: August 2015

Head and neck squamous cell carcinoma (HNSCC) have a propensity for aggressive growth and metastasis, with high morbidity and low 5-year survival rates. Despite advances in treatment, the overall survival rate has only modestly improved over the past several years. Herbal tea extract from the root and leaves of Arum palaestinum has been used to prevent and facilitate treatment of cancer in Palestine. Very few studies have addressed the mechanisms and antitumor efficacy of this neutraceutical. Here we tested the antitumor efficacy of synthetic formulations of Arum palaestinum extract (GZ17-S, -05.00 and -06.02) in preclinical models of HNSCC. Our preliminary data demonstrates that these formulations have antitumor efficacy in several tumor types including HNSCC, lung and ovarian cancer cells. We hypothesized that GZ17-06.02 inhibits phosphorylation of key molecules that mitigate HNSCC progression and induce apoptotic cell death.

Cytotoxicity of all the formulations was investigated on two HNSCC cell lines, OSC19 and UMSCC1. The GZ17-06.02 and -05.00 were found to be highly efficacious with low ED50 values (11.85 μg/ml and 16.40 μg/ml, respectively) for OSC19 and (10.86 μg/ml and 11.60 μg/ml, respectively) UMSCC1 cells at 72h. We determined the efficacy of GZ17 formulations in mitigating HNSCC invasion and migration. Among the formulations tested, GZ17-06.02 was most efficacious in significantly reducing invasion (37.33%) and migration (12.66%) of OSC19 cells compared to vehicle control (p&lt;0.001). Further, GZ17-06.02 induced cytotoxicity through Caspase-3 and PARP cleavage in HNSCC cells. Flow cytometric analyses of GZ17-06.02 treated HNSCC revealed a significant reduction in cells in the G1 phase and increased apoptosis compared to vehicle control treated cells. In order to determine the molecular mechanism regulating these effects, we assessed the levels of phosphorylated proteins. It was observed that phosphorylation of several signal transducing molecules including MAPK, EGFR, Akt 1/2/3, checkpoint kinase (chk2), proto oncogene tyrosine-kinase (Src) and signal transducer and activator of transcription2 (STAT2) were reduced in OSC19 cells treated with GZ17-06.02 compared to vehicle control. Further, we tested the in vivo antitumor efficacy of all formulations on HNSCC xenografts. All formulations demonstrated antitumor efficacy up on intratumoral administration of 15 mg/kg/d. GZ17-06.02 was most efficacious in significantly reducing the tumor volume compared to the vehicle control treated tumors (p&lt;0.001). All formulations were well tolerated. We are now testing the antitumor efficacy of GZ17-06.02 on systemic delivery (oral gavage) in a patient-derived xenograft model of HNSCC. In conclusion, the synthetic versions of Arum Palaestinum demonstrate potent therapeutic potential in HNSCC through down-regulation of key signaling molecules and the induction of apoptosis.

Citation Format: Vikalp Vishwakarma, Kyle Crooker, Vusala Snyder, Jeffrey Straub, Caitlin Cole, Annie Lee, Lisa Stehno Bittel, Sufi Thomas. Antitumor efficacy of synthetic formulations of active components in Arum palaestinum extracts in head and neck squamous cell carcinoma. [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 5540. doi:10.1158/1538-7445.AM2015-5540