title: Isocudraxanthone K induces growth inhibition and apoptosis in oral cancer cells via hypoxia inducible factor-1α.
abstract: Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-α in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1α activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1α inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.
authors.affiliation: Department of Prosthodontics, Dongtan Sacred Heart Hospital, Hallym University, Dongtan, Republic of Korea.
authors.forename: Mee-Ran
authors.initials: MR
authors.lastname: Shin
authors.affiliation: Department of Oral and Maxillofacial Pathology, and Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, 1 Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Hwa-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Soo-Kyung
authors.identifier: 0000-0001-5535-5990
authors.initials: SK
authors.lastname: Kang
authors.affiliation: Department of Oral Medicine, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Q-Schick
authors.initials: QS
authors.lastname: Auh
authors.affiliation: Department of Oral and Maxillofacial Pathology, and Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, 1 Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Young-Man
authors.initials: YM
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Wonkwang University, Iksan 570-749, Republic of Korea.
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Oral and Maxillofacial Pathology, and Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, 1 Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D029586:Moraceae / Q000737:chemistry*; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024301:Plant Bark / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C000595707:BCL2 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; C498143:RELA protein, human; D051996:Transcription Factor RelA; D044004:Xanthones; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases
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