Identification of Natural Compounds to Inhibit Sonic Hedgehog Pathway in Oral Cancer

Abstract

Background: Conventional treatment resistance remains a significant problem in cancer care. Cancer stem cells might play a major role in treatment resistance, and as a result, basic stem cell pathways are instrumental in cancer. Sonic Hedgehog signaling has not been widely studied in oral cancer, and being one of the major cancer stem cell pathways, targeting it with natural compounds could open many opportunities in the treatment scenario. Objective: The objective of the study was to identify the role of various natural compounds as an anti-cancer agent for oral cancer by targeting the Hedgehog signaling pathway. Methods: The selection of natural compounds were identified through literature review and NPACT database. The protein (3M1N and 3MXW) and ligand molecules were retrieved through the PDB and PubChem database. To carry out docking experiments, the AutoDock 4.2 program was used to study the interaction between the identified protein and ligand. Results: Among the 13 identified natural compounds, the top three were selected based on their binding energy. The higher the binding energy on the negative side, the better the interaction formed between protein and ligand. The natural compound showing best results with 3M1N protein were Butein, Biochanin-A, and Curcumin, whereas, with 3MXW, Zerumbone, Curcumin, and Butein were identified. Conclusion: The identified natural compounds have shown better binding energy to bind the Hh ligands in the absence/presence of a known Sonic Hedgehog inhibitor. Based on the results, natural compounds can be utilized in the current treatment modality for oral cancer either as an individual anti-cancer agent or in combination with the known Sonic Hedgehog inhibitor to curb the increasing incidence rate. Yet, in-vitro evidence in lab setup is required.

The Role of Hedgehog Signaling Pathway in Head and Neck Squamous Cell Carcinoma

“…Some of them are currently used in the treatment of various tumors. Interestingly, several natural compounds like curcumin and resveratrol inhibit HH signaling [ 180 , 181 ].…”

Recent Advances in the Targeting of Head and Neck Cancer Stem Cells

“…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.…”

The role of Hedgehog and Notch signaling pathway in cancer

“…2. Ligand dependency: (i) Auto-secretory ligand-dependent activation, in which tumor cells respond to increased expression of their HH ligands in a cell-autonomous manner (i.e., glioblastoma [ 201 ], neck squamous cell carcinoma [ 202 , 203 ], and lung [ 204 ], breast [ 205 , 206 ], ovarian [ 207 ], stomach [ 208 , 209 ], esophageal [ 210 ], pancreatic [ 211 ], and prostate cancers); (ii) Paracrine-ligand-dependent model, in which Hh ligands produced and released by tumor cells switch on HH signaling in the peripheral stroma, in turn facilitating tumor expansion and metastasis, and creating a positive feedback loop (i.e., prostate, ovarian [ 212 – 214 ], pancreatic [ 215 ] and colorectal cancers [ 216 , 217 ]); (iii) Reverse paracrine ligand-dependent signaling activation, indicates that Hh ligands are secreted from the stroma and received by tumor cells (i.e., multiple myeloma, lymphoma [ 218 ], and leukemia [ 219 , 220 ]). 3.…”