title: Targeting cholesterol with β-cyclodextrin sensitizes cancer cells for apoptosis.
abstract: We found that targeting cholesterol with beta-cyclodextrin (bCD) and its derivatives disrupted signal transduction between PI3K and AKT, attenuating AKT pro-survival signals. In their absence, 2-deoxyglucose (2DG) caused anti-apoptotic protein Mcll to dissociate from pro-apoptotic Bak at mitochondria. Normally Bak is sequestered by its inhibitory associations with Mcll and Bcl-xL, and only when Bak is released from both, is it free to form oligomers through which cytochrome c can escape into the cytosol. Thus an addition of a bcl-2 antagonist dissociates Bak from Bcl-xL, triggering cytochrome c release and inducing apoptosis. 2DG-bCD can also sensitize type II cancer cells for TRAIL-mediated apoptosis.
authors.affiliation: Kansai Medical University, Department of Anesthesiology, Hirakata 573-1010, Japan. Electronic address: rudy.yamaguchi@hushmail.com.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Perkins
authors.affiliation: Kansai Medical University, Department of Anesthesiology, Hirakata 573-1010, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D003433:Crosses, Genetic; D003847:Deoxyglucose / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D047392:beta-Cyclodextrins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000814:Aniline Compounds; D000924:Anticholesteremic Agents; D000963:Antimetabolites; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D013449:Sulfonamides; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003847:Deoxyglucose; C031215:betadex; C528561:navitoclax
keywords: 2-Deoxyglucose; ABT-263; AKT; Apoptosis; Bcl2; Beta-cyclodextrin; Cancer; Cancer therapy; Epidermal growth factor; Insulin-like growth factor 1; Mcl1; Mitochondria; Pancreatic cancer; Phosphoinositide 3-kinase; Pro-survival signal; Receptor tyrosine kinase; TNF-related apoptosis-inducing ligand