1α,25-Dihydroxyvitamin D3 synergistically enhances anticancer effects of ginsenoside Rh2 in human prostate cancer cells

Mohamed Ben-Eltriki; Subrata Deb; Emma S Tomlinson Guns

doi:10.1016/j.jsbmb.2021.105828

1α,25-Dihydroxyvitamin D₃ synergistically enhances anticancer effects of ginsenoside Rh2 in human prostate cancer cells

J Steroid Biochem Mol Biol. 2021 May:209:105828. doi: 10.1016/j.jsbmb.2021.105828. Epub 2021 Jan 22.

Authors

Mohamed Ben-Eltriki¹, Subrata Deb², Emma S Tomlinson Guns³

Affiliations

¹ Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada; Therapeutics Initiative, Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
² Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, 18301 N. Miami Avenue, Miami, FL, 33169, USA. Electronic address: sdeb@alumni.ubc.ca.
³ Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada. Electronic address: emmabluetube@gmail.com.

PMID: 33493594
DOI: 10.1016/j.jsbmb.2021.105828

Abstract

1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃, commonly known as calcitriol), the most active metabolite of vitamin D₃, and ginsenoside Rh2 can regulate cellular differentiation and proliferation proteins. The purpose of the present study was to assess the effect of 1,25(OH)₂D₃ on the anticancer activities of Rh2 in human prostate cancer cells such as androgen-dependent LNCaP and androgen-independent C4-2 in vitro. The effects of treatment with 1,25(OH)₂D₃ or Rh2, either alone or in combination, on prostate cancer cells were evaluated through tetrazolium-based cell viability assay, BrdU cell proliferation rate estimation assay, and Western blot protein expression analyses of nuclear receptors (androgen receptor and vitamin D receptors) and apoptotic proteins (Bcl-2, Bax, and Caspase 3). The Combination Indices (CI) and Dose Reduction Indices (DRI) of 1,25(OH)₂D₃ and Rh2 were calculated to determine synergistic anticancer activity using Calcusyn software (Biosoft, Cambridge, UK). The cell viability assay data indicate that Rh2 treatment alone inhibited cell viability in a concentration-dependent manner and the addition of 10 nM 1,25(OH)₂D₃ to Rh2 significantly enhanced its ability to reduce cell viability up to 80 % in both the cell lines. Similarly, addition of 10 nM 1,25(OH)₂D₃ to Rh2 significantly lowered its IC₅₀ values for cell proliferation from the range of 32-65 μM to 14-8 μM in LNCaP and C4-2 cells. In addition, protein expression analyses indicated that the combined treatment with Rh2 and 1,25(OH)₂D₃ led to greater downregulation of androgen receptor expression compared to single agent exposure. Similarly, the presence of 1,25(OH)₂D₃ synergistically increased the pro-apoptotic actions of Rh2 in both the cell lines. Overall, 1,25(OH)₂D₃ augments the Rh2-mediated anticancer effects through stimulating apoptosis and reduced cell proliferation which suggests that synergism of this combination may lead to potential lower need of the active vitamin D₃ and limited toxicity from it.

Keywords: 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)); Ginsenoside Rh2; Prostate cancer; Synergism; Vitamin D receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis
Cell Proliferation
Drug Synergism*
Drug Therapy, Combination
Ginsenosides / pharmacology*
Humans
Male
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Tumor Cells, Cultured
Vitamin D / analogs & derivatives*
Vitamin D / pharmacology

Substances

Antineoplastic Agents
Ginsenosides
Vitamin D
1,25-dihydroxyvitamin D
ginsenoside Rh2