# Recent Advances in the Targeting of Head and Neck Cancer Stem Cells
## 6 Therapeutic Targeting of CSCs
### Targeting by Natural Compounds  
Curcumin, epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol, and genistein are the most studied naturally occurring agents with anti-cancer stem cell properties [174; 175; 176]. For example, resveratrol and oxyresveratrol inhibit the expression of cancer stem-cell markers and could possibly target cancer stem cells in a hypoxia-associated tumor [177]. Even though many compounds that could be exploited in CSC-specific therapy are emerging and being tested every day, there are not many naturally occurring compounds identified and evaluated for HNSCC yet.  
Different Chinese herbs have been used in cancer medicine for years, and some of the active ingredients have been shown to be effective in CSC suppression as well. For example, the bioactive macrocyclic diterpenoid compound ovatodiolide, purified from the herb _Anisomeles indica_ (L.) _Kuntze_, used in Chinese traditional herbal medicine, decreased the tumor-initiating potential of orospheres in a mouse xenograft model [178]. Polysaccharidesides from _Ganoderma lucidum_, an oriental fungus that has been used for promoting health and longevity in China, Japan, and other Asian countries, have also shown such an effect in OSCC. These specific polysaccharides decreased colony formation and impaired sphere formation, as well as downregulated EMT and ABC markers of chemoresistance [179]. Butylidenephthalide, a bioactive phthalide compound from _Angelica sinensis_, which is also an herb used in Chinese medicine, diminishes CSC properties in an oral carcinoma model [180].  
Few novel natural compounds have been found in a recent study aimed at finding the inhibitors of the SHh pathway in oral cancer: Butein, Biochanin-A, and Curcumin [181]. It remains to test these compounds in CSC models to see if they are effective, considering the importance of the SHh pathway in CSC. Honokiol, a lignan (low molecular weight polyphenol) isolated from different parts of trees belonging to the genus _Magnolia_, has shown an inhibitory effect on cell survival and self-renewal of oral carcinoma stem cells. It can suppress CSC markers ALDH1 and CD44, decrease migration and invasion, reduce secretion of IL-6, and decrease phosphorylation of STAT3. This lignan can also synergize with cisplatin in inhibiting cell survival [182]. Interestingly, another compound from _Magnolia_, magnolol, also suppresses the oral cancer stemness properties [183]. The most abundant diterpene lactone from the leaves and stem of _Andrographis paniculata_ (_Burm. f_) _Ness_, an herbal plant generally cultivated in India, Thailand, and China and used as a traditional medicine, is called andrographolide. This substance is effective in therapy against CSCs in oral carcinomas. It can reduce oncogenicity and increase the radiosensitivity of oral CSCs via the increased expression of miR-218 resulting in the downregulation of Bmi-1, a protein important for self-renewal of CSC [184]. Mycelium from the fungus _Antrodia cinnamonea_ and its ethyl acetate extracts have antiproliferative effects against all types of CSCs, including HNSCC CSCs. Additionally, CSC treatment with _A. cinnamonea_ increased the effect of chemo- and radiotherapy [185]. Gallotannin extract from _Bouea macrophylla_ seed, a plant that has a fruit similar to a mango, showed an antiproliferative effect in HNSCC CSCs, while it also enhanced radiosensitivity [186]. Furthermore, propolis has been shown to reduce stemness in HNSCC [187]. Paris saponin II from the plant _Paris polyphylla_ Smith var. _yunnanensis_, which is used as an anticancer drug in traditional Chinese medicine, causes reduced sphere formation [188]. As for the well-known vegetables, radish (_Raphanus sativus_ L.) seed extracts induce apoptosis and downregulate \(\beta\)-catenin in oral CSCs [189], while broccoli extract (sulforaphane) increases the cytotoxicity of cisplatin and 5-FU and inhibits sphere formation and tumor progression [190].