PT19c, Another Nonhypercalcemic Vitamin D2 Derivative, Demonstrates Antitumor Efficacy in Epithelial Ovarian and Endometrial Cancer Models

Nada Kawar; Shannon Maclaughlan; Timothy C Horan; Alper Uzun; Thilo S Lange; Kyu K Kim; Russell Hopson; Ajay P Singh; Preetpal S Sidhu; Kyle A Glass; Sunil Shaw; James F Padbury; Nicholi Vorsa; Leggy A Arnold; Richard G Moore; Laurent Brard; Rakesh K Singh

doi:10.1177/1947601913507575

PT19c, Another Nonhypercalcemic Vitamin D2 Derivative, Demonstrates Antitumor Efficacy in Epithelial Ovarian and Endometrial Cancer Models

Genes Cancer. 2013 Nov;4(11-12):524-34. doi: 10.1177/1947601913507575.

Authors

Nada Kawar¹, Shannon Maclaughlan², Timothy C Horan¹, Alper Uzun³, Thilo S Lange¹, Kyu K Kim¹, Russell Hopson⁴, Ajay P Singh⁵, Preetpal S Sidhu⁶, Kyle A Glass³, Sunil Shaw³, James F Padbury³, Nicholi Vorsa⁵, Leggy A Arnold⁶, Richard G Moore¹, Laurent Brard⁷, Rakesh K Singh¹

Affiliations

¹ Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI, USA.
² Stanford Women's Cancer Center, Stanford University, Stanford, CA, USA.
³ Department of Pediatrics, Women and Infants' Hospital, Brown University, Providence, RI, USA.
⁴ Department of Chemistry, Brown University, Providence, RI, USA.
⁵ Department of Plant Biology and Pathology, Rutgers University, New Brunswick, NJ, USA.
⁶ Department of Chemistry and Biochemistry, University of Wisconsin, Milwaukee, WI, USA.
⁷ Department of Obstetrics and Gynecology, School of Medicine, Southern Illinois University, Springfield, IL, USA.

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.

Keywords: antitumor efficacy; endometrial cancer; hypercalcemia; ovarian cancer; vitamin D.

Grants and funding

R01 CA136491/CA/NCI NIH HHS/United States