RamyAlbady Alashry¹, EssamTaher Gaballa² and Hassan Ahmed Abd Alghaffar³ 1- Teaching assistant, Department of Oral Pathology, Faculty of Dentistry, Mansoura University, Egypt. 2- Vice dean of Student and Teaching affairs,Professor of  Oral Pathology, Faculty of Dentistry,Mansoura University, Egypt. 3- Director of Molecular Haematology Laboratory, Professor of Haematology, Faculty of Medicine, Mansoura University, Egypt. Abstract: Background:Head and neck squamous cell carcinoma (HNSCC), and laryngeal squamous cell carcinoma (LSCC) in particular, are always recorded to have unfavorable prognosis due to local invasion, regional lymph node and distant metastases, and resistance to conventional chemoradiotherapy. Regarding the new model of carcinogenesis, the Cancer Stem Cells (CSCs) are potentially responsible for the genesis, sustained growth, metastatic tumor spread, and even the chemoradioresistance. Most of the current larynx cancer therapies are generally aimed at the global mass of tumor, targeting the non-tumorigenic cells, and unfortunately sparing the tumorigenic CSCs. It therefore appears reasonable to consider that the novel treatment approaches to larynx cancer should be directed against CSCs. Recently, phytochemicals and herbs have been suggested to be potential sources of therapeutics for CSCs eradication. The current study introduced two renowned herbal ingredients, namely Honokiol and the green tea extract (Epigallocatechin-3-gallate) as LSCC treatment options because of their easy accessibility, selectivity and reduced incidence of side effects. The molecular mechanisms underpinning their cytotoxic effects on CSCs were further elucidated. Materials&methods:The CD44^high cells were isolated from HEp-2 laryngeal cancer cell line, and characterized their functional features of self-renewal by tumorsphere formation assay. Moreover, the expression levels of the pluripotency genes in CD44^high and CD44^low cells were measured by real-time qRT-PCR.Thereafter, treatment of HEp-2 CD44^high CSCs with either EGCG or HNK was commenced, then their anti-proliferative impacts by MTT assay were demonstrated. Finally, the underlying mechanisms of EGCG and HNK potential anti-cancer effects were investigated by real-time qRT-PCR screening for expression of genes involved in self-renewal and apoptosis. Results:In vitro self-renewal capacity of CD44^high cells was observed by inducing three-dimensional tumorspheres formation. The statistical analysis revealed elevated expression levels of the pluripotency genes (BMI-1, OCT-4, and SOX2) in CD44^high cells that significantly exceeded those in CD44^low cells.Both EGCG and HNK decreased the viability of CD44^high cells in a dose-dependent manner, but the statistical analysis showed that growth inhibitory efficiency of EGCG on CD44^high CSCs exceeded those of HNK.Significant suppression of Notch1 was prominent in EGCG-treated CD44^highcells, but HNK showed higher proficiency in inhibiting β-catenin and PTCH-1.In CSCs, both EGCG and HNK triggered significant suppression of BCL-2, and upregulation of BAX. p53 was upregulated in HNK-treated CSCs, in contrast to its downregulation in HEp-2 cells treated with EGCG. Conclusion:CD44^highLSCC cells were highly enriched for CSC properties. EGCG harbored a preeminent selective targeting potential on the LSCC CSCs. EGCG outshined HNK as a potent suppressor of Notch signaling pathway. Nonetheless, HNK privileged in downregulating β-catenin and Sonic Hedgehog (SHH) signaling pathways. Both EGCG and HNK engaged the BCL-2 family-regulated intrinsic mitochondrial apoptotic pathway in LSCC cells, but EGCG induced apoptosis viap53-independent pathway, whereas HNK triggered apoptosis via p53-dependent pathway.