Abstract B116: Mechanistic insights into the antitumor efficacy of nutraceutical GZ17-06.02, a highly effective formulation of Arum palaestinum extract, on head and neck squamous cell carcinoma
Authors: New Jacob , Vishwakarma Vikalp , Kumar Dhruv , Crooker Kyle , Snyder Vusala , Shnayder Yelizaveta , Kakarala Kiran , Tsue Terance T. , Girod Douglas , Stehno-Bittel Lisa , Thomas Sufi M. 
Published: May 2016

Abstract
Although Arum palaestinum has been used as a natural prevention and treatment of cancer in Palestine for many years, few studies have examined its efficacy and mechanism of action. Chemically synthesized components of Arum palaestinum extract mixed in a ratio that was present in the natural extract were tested on head and neck squamous cell carcinoma (HNSCC), which affects annually 50,000 new people and causes 10,000 deaths a year in the US alone. We examined the effects of the nutraceutical on cell lines and patient-derived HNSCC tumors, and we delineated the mechanism of action. Among three formulations tested of Arum palaestinum (GZ17-S, a fortified version of the plant extract; GZ17-05.00, 16 components of the original plant extract; and GZ17-06.02, 3 components of the original plant extract), we found formulation GZ17-06.02 to be the most effective at reducing cancer cell proliferation, migration, and invasion. Further, GZ17-06.02 decreased angiogenesis in a tubule formation assay. When combined with a standard chemotherapeutic, cisplatin, GZ17-06.02 decreased cancer cell proliferation to a similar level of cisplatin, and enhanced the effect of cisplatin when used in combination. In comparison to radiotherapy, GZ17-06.02 performed better at reducing HNSCC cell proliferation than 3, 6, or 9 gy of radiation alone, and sequential treatment of HNSCC with radiation followed by GZ17-06.02 did not enhance the cytotoxic effects compared to GZ17-06.02 alone. We identified molecular signaling cascades inhibited by GZ17-06.02, including Src, ERK1/2, EGFR, AKT1/2/3, STAT-2, and Chk2, and we performed molecular docking analyses between GZ17-06.02 components and EGFR and AKT. We found that GZ17-06.02 components bind simultaneously at distinct binding sites of the kinase domains of EGFR and AKT. We found GZ17-06.02 induced significant apoptosis in HNSCC cells, increasing cleaved PARP, and activating caspase-3. Intratumoral injections of GZ17-06.02 were well tolerated in mice, and inhibited the growth and induced necrosis of HNSCC xenografts when injected intratumorally. In addition, orally administered GZ17-06.02 not only mitigated the growth of patient-derived HNSCC xenografts, but significantly decreased the tumor volume compared to the initially implanted tumor. Response to treatment correlated with a reduction in ERK1/2, which establishes it as an excellent biomarker for future clinical trials. Taken together, we demonstrate GZ17-06.02 as a highly effective nutraceutical, and pave the way for future clinical application in HNSCC.
Citation Format: Jacob New, Vikalp Vishwakarma, Dhruv Kumar, Kyle Crooker, Vusala Snyder, Yelizaveta Shnayder, Kiran Kakarala, Terance T. Tsue, Douglas Girod, Lisa Stehno-Bittel, Sufi M. Thomas. Mechanistic insights into the antitumor efficacy of nutraceutical GZ17-06.02, a highly effective formulation of Arum palaestinum extract, on head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B116.