title: 17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis: Structure-Activity Relationships.
abstract: Renal cell carcinoma (RCC) is a cancer with poor prognosis, and the 5-year survival rate of patients with metastatic RCC is 5-10%. Consequently, treatment of metastatic RCC represents an unmet clinical need. Screening of a 50 000-member library of natural and synthetic compounds for sensitizers of RCC cells to TRAIL-mediated apoptosis led to identification of the 17β-hydroxywithanolide (17-BHW), withanolide E (1), as a promising lead. To explore structure-activity relationships, we obtained natural and semisynthetic withanolides 1, 2a, 2c, and 3-36 and compared their ability to sensitize TRAIL-mediated apoptosis in a panel of renal carcinoma cells. Our findings revealed that 17-BHWs with a α-oriented side chain are superior to known TRAIL-sensitizing withanolides belonging to withaferin A class with a β-oriented side chain and demonstrated that the 17-BHW scaffold can be modified to enhance sensitization of RCCs to TRAIL-mediated apoptosis, thereby assisting development of natural-product-inspired drugs to treat metastatic RCC.
authors.affiliation: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 E. Valencia Road, Tucson, Arizona 85706, United States.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Xu
authors.affiliation: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.|Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland 21702, United States.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Brooks
authors.affiliation: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 E. Valencia Road, Tucson, Arizona 85706, United States.
authors.forename: E M Kithsiri
authors.initials: EM
authors.lastname: Wijeratne
authors.affiliation: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.|Molecular Targets Laboratory, National Cancer Institute-Frederick , Frederick, Maryland 21702, United States.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Henrich
authors.affiliation: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.|Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland 21702, United States.
authors.forename: Poonam
authors.initials: P
authors.lastname: Tewary
authors.affiliation: Basic Research Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States.|Cancer and Inflammation Program, National Cancer Institute-Frederick , Frederick, Maryland 21702, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.affiliation: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 E. Valencia Road, Tucson, Arizona 85706, United States.
authors.forename: A A Leslie
authors.identifier: 0000-0001-9663-3600
authors.initials: AA
authors.lastname: Gunatilaka
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D032341:Withania / Q000737:chemistry; D054358:Withanolides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C096968:17-hydroxywithanolide K; C554450:4-hydroxywithanolide E; D000972:Antineoplastic Agents, Phytogenic; D053221:TNF-Related Apoptosis-Inducing Ligand; D054358:Withanolides; C009684:withaferin A; D004875:Ergosterol