Head and neck cancer, which includes epithelial malignancies of various origins of the pharynx, larynx, sinuses, oral cavity and nasal cavity, is the sixth most common type of cancer in the world. The primary treatment modality for head and neck cancer involves surgery and aggressive concomitant chemo and radiotherapies. These treatments are associated with significant complications, which are potentially life‐threatening. We wanted to test plant‐derived compounds for anticancer activity against head and neck cancer. Some phytochemicals have been shown to exhibit anticancer effects, and inhibit tumor development and growth in animal models. We screened several phytochemicals on two head and neck cancer lines, SCC‐40 and UM‐SCC‐47 to identify potential anticancer compounds. We identified cucurbitacin B to be a highly potent inhibitor of cell proliferation and viability. Cucurbitacin B inhibited proliferation of both SCC‐40 cells and UM‐SCC‐47 at very low concentrations (0.5–2 μM). The mechanism of inhibition appears to be by induction of apoptosis and autophagy in the treated cells.Support or Funding InformationAG and MH are supported by DeNardo Education and Research Foundation Fellowship. Financial support for this study was provided by a Seed Grant from Saint Louis University.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.