title: PT19c, Another Nonhypercalcemic Vitamin D2 Derivative, Demonstrates Antitumor Efficacy in Epithelial Ovarian and Endometrial Cancer Models.
abstract: Hypercalcemia remains a major impediment to the clinical use of vitamin D in cancer treatment. Approaches to remove hypercalcemia and development of nonhypercalcemic agents can lead to the development of vitamin D-based therapies for treatment of various cancers. In this report, in vitro and in vivo anticancer efficacy, safety, and details of vitamin D receptor (VDR) interactions of PT19c, a novel nonhypercalcemic vitamin D derived anticancer agent, are described. PT19c was synthesized by bromoacetylation of PTAD-ergocalciferol adduct. Broader growth inhibitory potential of PT19c was evaluated in a panel of chemoresistant breast, renal, ovarian, lung, colon, leukemia, prostate, melanoma, and central nervous system cancers cell line types of NCI60 cell line panel. Interactions of PT19c with VDR were determined by a VDR transactivation assay in a VDR overexpressing VDR-UAS-bla-HEK293 cells, in vitro VDR-coregulator binding, and molecular docking with VDR-ligand binding domain (VDR-LBD) in comparison with calcitriol. Acute toxicity of PT19c was determined in nontumored mice. In vivo antitumor efficacy of PT19c was determined via ovarian and endometrial cancer xenograft experiments. Effect of PT19c on actin filament organization and focal adhesion formation was examined by microscopy. PT19c treatment inhibited growth of chemoresistant NCI60 cell lines (log10GI50 ~ -4.05 to -6.73). PT19c (10 mg/kg, 35 days) reduced growth of ovarian and endometrial xenograft tumor without hypercalcemia. PT19c exerted no acute toxicity up to 400 mg/kg (QDx1) in animals. PT19c showed weak VDR antagonism, lack of VDR binding, and inverted spatial accommodation in VDR-LBD. PT19c caused actin filament dysfunction and inhibited focal adhesion in SKOV-3 cells. PT19c is a VDR independent nonhypercalcemic vitamin D-derived agent that showed noteworthy safety and efficacy in ovarian and endometrial cancer animal models and inhibited actin organization and focal adhesion in ovarian cancer cells.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Nada
authors.initials: N
authors.lastname: Kawar
authors.affiliation: Stanford Women's Cancer Center, Stanford University, Stanford, CA, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Maclaughlan
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Horan
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Alper
authors.initials: A
authors.lastname: Uzun
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Thilo S
authors.initials: TS
authors.lastname: Lange
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Kyu K
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Brown University, Providence, RI, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Hopson
authors.affiliation: Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Singh
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, WI, USA.
authors.forename: Preetpal S
authors.initials: PS
authors.lastname: Sidhu
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Glass
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaw
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.affiliation: Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Nicholi
authors.initials: N
authors.lastname: Vorsa
authors.affiliation: Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, WI, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Southern Illinois University, Springfield, IL, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
keywords: antitumor efficacy; endometrial cancer; hypercalcemia; ovarian cancer; vitamin D