title: Sanguinarine Induces Apoptosis of Human Oral Squamous Cell Carcinoma KB Cells via Inactivation of the PI3K/Akt Signaling Pathway.
abstract: Preclinical Research Sanguinarine, an alkaloid isolated from the root of Sanguinaria canadensis and other plants of the Papaveraceae family, selectively induces apoptotic cell death in a variety of human cancer cells, but its mechanism of action requires further elaboration. The present study investigated the pro-apoptotic effects of sanguinarine in human oral squamous cell carcinoma KB cells. Sanguinarine treatment increased DR5/TRAILR2 (death receptor 5/TRAIL receptor 2) expression and enhanced the activation of caspase-8 and cleavage of its substrate, Bid. Sanguinarine also induced the mitochondrial translocation of pro-apoptotic Bax, mitochondrial dysfunction, cytochrome c release to the cytosol, and activation of caspase-9 and -3. However, a pan-caspase inhibitor, z-VAD-fmk, reversed the growth inhibition and apoptosis induced by sanguinarine. Sanguinarine also suppressed the phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt in KB cells, while co-treatment of cells with sanguinarine and a PI3K inhibitor revealed synergistic apoptotic effects. However, pharmacological inhibition of AMP-activated protein kinase and mitogen-activated protein kinases did not reduce or enhance sanguinarine-induced growth inhibition and apoptosis. Collectively, these findings indicate that the pro-apoptotic effects of sanguinarine in KB cells may be regulated by a caspase-dependent cascade via activation of both intrinsic and extrinsic signaling pathways and inactivation of PI3K/Akt signaling. Drug Dev Res 77 : 227-240, 2016.   © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biology, New York University, New York, NY, 10012, USA.
authors.forename: Tae Kyung
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, College of Natural Sciences and Human Ecology, Dongeui University, Busan, 614-714, South Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Dental Hygiene, College of Health Sciences, Youngsan University, Yangsan, 626-790, South Korea.
authors.forename: Soon-Jeong
authors.initials: SJ
authors.lastname: Jeong
authors.affiliation: Department of Oral Histology and Developmental Biology, School of Dentistry, Chosun University, Gwangju, 501-759, South Korea.
authors.forename: Moon-Jin
authors.initials: MJ
authors.lastname: Jeong
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju, 690-756, South Korea.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Department of Urology, Chungbuk National University, College of Medicine and Institute for Tumor Research, Cheongju, 28644, South Korea.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Anti-Aging Research Center, Dongeui University, Busan, 614-714, South Korea.|Department of Biochemistry, Dongeui University College of Korean Medicine, Busan, 614-714, South Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines / Q000302:isolation & purification / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000302:isolation & purification / Q000494:pharmacology*; D007624:KB Cells; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D031681:Sanguinaria / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D007546:Isoquinolines; C005705:sanguinarine; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: PI3K/Akt; Sanguinarine; apoptosis; caspase