PMID- 35984397 OWN - NLM STAT- MEDLINE DCOM- 20230712 LR - 20230718 IS - 2769-707X (Electronic) IS - 2769-7061 (Linking) VI - 42 IP - 6 DP - 2023 Aug TI - Oroxylum indicum Stem Bark Extract Reduces Tumor Progression by Inhibiting the EGFR-PI3K-AKT Pathway in an In Vivo 4NQO-Induced Oral Cancer Model. PG - 573-587 LID - 10.1080/27697061.2022.2107583 [doi] AB - OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer. Its incidence is high in certain geographic regions, and it is correlated with chewing tobacco. Epidermal growth factor receptor (EGFR), induced by tobacco carcinogens, is overexpressed in OSCC, leading to poor prognosis. Thus, EGFR inhibitors are promising agents against OSCC. High cost and toxicity of existing EGFR inhibitors necessitate alternative EGFR-targeted therapy. Here, we tested the antitumor potential of ethyl acetate fraction of an ethnomedicinal tree, Oroxylum indicum stem bark extract (OIEA) in a 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis model. METHODS: OIEA was prepared by solvent extraction method, and subsequently its in vitro radical scavenging activities were measured. High-performance liquid chromatography (HPLC) analysis of OIEA was done to identify the constituent active compounds. Hemolytic, trypan blue exclusion, and MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assays were performed in normal and cancer cells to select an optimum dose of OIEA for antitumor activity study in 4NQO-induced oral cancer in F344 rats. Measurement of tumor volume, weight, and cell count was followed by tumor cell cycle analysis and comet and annexin V/Propidium Iodide (PI) assay. Pro-apoptotic markers were detected by western blot testing. Molecular docking was done to predict the interaction between OIEA active component and EGFR or phosphatidylinositol-3-kinase (PI3K), which was further validated biologically. Finally, hepatic and renal function testing and histopathology were performed. RESULTS: OIEA reduced tumor burden and increased survivability of the tumor-bearing rats significantly as compared to untreated tumor bearers. HPLC revealed oroxylin A as the predominant bioactive component in OIEA. Molecular docking predicted significant binding between oroxylin A and EGFR as well as PI3K, which was confirmed by western blot analysis of in vivo samples. OIEA also ameliorated hepato-, renal- and myelotoxicity induced by 4NQO. CONCLUSION: OIEA reduces 4NQO-induced OSCC by modulating the EGFR/PI3K/AKT signaling cascade and also ameliorated toxicity in tumor bearers. FAU - Parvin, Munia AU - Parvin M AD - Department of Zoology, West Bengal State University, Kolkata, West Bengal, India. FAU - Rahaman, Ashikur AU - Rahaman A AD - Department of Zoology, West Bengal State University, Kolkata, West Bengal, India. FAU - Sarkar, Arnab AU - Sarkar A AD - Department of Zoology, West Bengal State University, Kolkata, West Bengal, India. FAU - Debnath, Sudhan AU - Debnath S AUID- ORCID: 0000-0002-3913-9048 AD - Department of Chemistry, N.S. Mahavidyalaya, Udaipur, Tripura, India. FAU - De, Utpal Chandra AU - De UC AD - Department of Chemistry, Tripura University, Agartala, Tripura, India. FAU - Mandal, Deba Prasad AU - Mandal DP AD - Department of Zoology, West Bengal State University, Kolkata, West Bengal, India. FAU - Bhattacharjee, Shamee AU - Bhattacharjee S AUID- ORCID: 0000-0002-4371-5271 AD - Department of Zoology, West Bengal State University, Kolkata, West Bengal, India. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220819 PL - United States TA - J Am Nutr Assoc JT - Journal of the American Nutrition Association JID - 9918300687506676 RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - 0 (Plant Extracts) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Rats MH - Animals MH - *Mouth Neoplasms/chemically induced MH - Proto-Oncogene Proteins c-akt/analysis MH - Phosphatidylinositol 3-Kinases/analysis MH - Phosphatidylinositol 3-Kinase/analysis MH - *Carcinoma, Squamous Cell MH - Plant Bark/chemistry MH - Molecular Docking Simulation MH - Rats, Inbred F344 MH - Plant Extracts/pharmacology MH - ErbB Receptors/analysis MH - Squamous Cell Carcinoma of Head and Neck MH - *Head and Neck Neoplasms OTO - NOTNLM OT - 4-NQO OT - EGFR OT - Oral cancer OT - Oroxylum indicum OT - PI3K EDAT- 2022/08/20 06:00 MHDA- 2023/07/12 06:42 CRDT- 2022/08/19 10:43 PHST- 2023/07/12 06:42 [medline] PHST- 2022/08/20 06:00 [pubmed] PHST- 2022/08/19 10:43 [entrez] AID - 10.1080/27697061.2022.2107583 [doi] PST - ppublish SO - J Am Nutr Assoc. 2023 Aug;42(6):573-587. doi: 10.1080/27697061.2022.2107583. Epub 2022 Aug 19.