title: Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma.
abstract: Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether combinatorial treatment using AG1478 (EGFR tyrosine kinase inhibitor) and deguelin, which is a rotenoid isolated from the African plantMundulea sericea, could enhance the anti-tumor effects of AG1478 in HNSCC. For Ca9-22 cells withEGFR,KRAS, andPIK3CAwild types, AG1478 alone suppressed both phosphorylated levels of ERK and AKT and induced apoptosis. On the contrary, for HSC-4 cells withEGFRandKRASwild types, and aPIK3CAmutant, AG1478 alone did not suppress the phosphorylated level of AKT nor induce apoptosis, while it suppressed ERK phosphorylation. Forced expression of constitutively activePIK3CA(G1633A mutation) significantly reduced the apoptotic effect of AG1478 on thePIK3CAwild-type Ca9-22 cells. When HSC-4 cells with thePIK3CAG1633A mutation were treated with a combination of AG1478 and deguelin, combination effects on apoptosis induction were observed through the inhibition of the AKT pathway. These results suggest that the combination of EGFR tyrosine kinase inhibitor with deguelin is a potential therapeutic approach to treatPIK3CA-mutated HNSCC.
authors.affiliation: Department of General Clinical Medicine, Ohu University School of Dentistry, 31-1, Mitsumido, Tomita-machi, Koriyama City, Fukushima 963-8611, Japan. y-baba@den.ohu-u.ac.jp.
authors.forename: Yuh
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, 31-1, Mitsumido, Tomita-machi, Koriyama City, Fukushima 963-8611, Japan. t-maeda@den.ohu-u.ac.jp.
authors.forename: Toyonobu
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, 31-1, Mitsumido, Tomita-machi, Koriyama City, Fukushima 963-8611, Japan. at-suzuki@den.ohu-u.ac.jp.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Ohu University School of Dentistry, 31-1, Mitsumido, Tomita-machi, Koriyama City, Fukushima 963-8611, Japan. s-takada@den.ohu-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takada
authors.affiliation: National Institute of Sensory Organs, National Tokyo Medical Center, 2-5-1, Higashigaoka, Meguro, Tokyo 152-8902, Japan. fujiimasato@kankakuki.go.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Oral Function and Molecular Biology, Ohu University School of Dentistry, 31-1, Mitsumido, Tomita-machi, Koriyama City, Fukushima 963-8611, Japan. yasumasa-kato@umin.ac.jp.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Kato
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; D012402:Rotenone; C101044:RTKI cpd; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C107676:deguelin
keywords: AKT; PIK3CA; deguelin; epidermal growth factor receptor (EGFR); head and neck squamous cell carcinoma (HNSCC)