title: Tumor-specific cytotoxicity and type of cell death induced by gefitinib in oral squamous cell carcinoma cell lines.
abstract: Gefitinib is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor. The present study was aimed at evaluating the antitumor activity of gefitinib alone or in combination with other antitumor agents. Gefitinib showed higher cytotoxicity against five human tumor cell lines (HSC-2, HSC-3, HSC-4, T98G and U87MG) than against three human normal oral cells (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF). Gefitinib showed little or no growth stimulation effects at lower concentrations (so-called hormetic effect). Non-cytotoxic concentration of gefitinib effectively enhanced the cytotoxicity of docetaxel against HSC-2 and T98G cell, but failed to enhance the cytotoxicity of other antitumor agents (mitoxantrone, doxorubicin, methotrexate, cisplatin, sodium ascorbate, sodium fluoride) or herbal extracts (Drynaria baronii, Angelica sinensis and Cornus officinalis Sieb. et Zucc). Gefitinib alone and combined with docetaxel induced internucleosomal DNA fragmentation and caspase-3 activation in human promyelocytic leukemia HL-60 cells, but not in HSC-2 or T98G cells. Combination treatment with gefitinib and docetaxel induced the formation of acidic organelles (stained with acridine orange) and mitochondrial shrinkage, vacuolization and production of autophagosome and the loss of cell surface microvilli, without destruction of cell surface and nuclear membranes in HSC-2 and T98G cells (demonstrated by transmission electron microscopy), suggesting the induction of autophagy in HSC-2 and T98G cells.
authors.affiliation: Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan. chuqing@fmmu.edu.cn
authors.forename: Qing
authors.initials: Q
authors.lastname: Chu
authors.forename: Osamu
authors.initials: O
authors.lastname: Amano
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kanda
authors.forename: Shiro
authors.initials: S
authors.lastname: Kunii
authors.forename: Qintao
authors.initials: Q
authors.lastname: Wang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000008:administration & dosage; D001343:Autophagy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D000077156:Gefitinib; D018922:HL-60 Cells; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008942:Mitoxantrone / Q000008:administration & dosage; D009055:Mouth / Q000187:drug effects*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D011799:Quinazolines / Q000008:administration & dosage; D012969:Sodium Fluoride / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D010936:Plant Extracts; D011799:Quinazolines; D004317:Doxorubicin; D012969:Sodium Fluoride; D008942:Mitoxantrone; D053148:Caspase 3; D001205:Ascorbic Acid; D002945:Cisplatin; D000077156:Gefitinib; D008727:Methotrexate