title: Differential antitumor effects of vitamin D analogues on colorectal carcinoma in culture.
abstract: Colorectal cancer (CRC) is an emerging global problem with the rapid increase in its incidence being associated with an unhealthy lifestyle. Epidemiological studies have shown that decreased levels of vitamin D3 significantly increases the risk of CRC. Furthermore, negative effects of vitamin D3 deficiency can be compensated by appropriate supplementation. Vitamin D3 was shown to inhibit growth and induce differentiation of cancer cells, however, excessive vitamin D3 intake leads to hypercalcemia. Thus, development of efficient vitamin D3 analogues with limited impact on calcium homeostasis is an important scientific and clinically relevant task. The aims of the present study were to compare the antiproliferative potential of classic vitamin D3 metabolites (1α,25(OH)2D3 and 25(OH)D3) with selected low calcemic analogues (calcipotriol and 20(OH)D3) on CRC cell lines and to investigate the expression of vitamin D-related genes in CRC cell lines and clinical samples. Vitamin D3 analogues exerted anti-proliferative effects on all CRC cell lines tested. Calcipotriol proved to be as potent as 1α,25(OH)2D3 and had more efficacy than 20-hydroxyvitamin D3. In addition, the analogs tested effectively inhibited the formation of colonies in Matrigel. The expression of genes involved in 1α,25(OH)2D3 signaling and metabolism varied in cell lines analysed, which explains in part their different sensitivities to the various analogues. In CRC biopsies, there was decreased VDR expression in tumor samples in comparison to the surgical margin and healthy colon samples (p<0.01). The present study indicates that vitamin D3 analogues which have low calcemic activity, such as calcipotriol or 20(OH)D3, are very promising candidates for CRC therapy. Moreover, expression profiling of vitamin D-related genes is likely to be a powerful tool in the planning of anticancer therapy. Decreased levels of VDR and increased CYP24A1 expression in clinical samples underline the importance of deregulation of vitamin D pathways in the development of CRC.
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: J M
authors.initials: JM
authors.lastname: Wierzbicka
authors.affiliation: Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Binek
authors.affiliation: Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Ahrends
authors.affiliation: Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: J D
authors.initials: JD
authors.lastname: Nowacka
authors.affiliation: Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Szydłowska
authors.affiliation: Students Scientific Association BIO‑MED, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Ł
authors.initials: Ł
authors.lastname: Turczyk
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Wąsiewicz
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: P M
authors.initials: PM
authors.lastname: Wierzbicki
authors.affiliation: Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology of the University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Sądej
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley WA, Australia.
authors.forename: R C
authors.initials: RC
authors.lastname: Tuckey
authors.affiliation: Department of Dermatology, University of Alabama Birmingham, VA Medical Center, Birmingham, AL 35294, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Slominski
authors.affiliation: Department of General Surgery, Hospital Ministry Internal Affairs, 80104 Gdańsk, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Chybicki
authors.affiliation: Department of Hepatology and Gastroenterology, Faculty of Medicine, Medical University of Gdańsk, 80210 Gdańsk, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Adrych
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Z
authors.initials: Z
authors.lastname: Kmieć
authors.affiliation: Department of Histology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: M A
authors.initials: MA
authors.lastname: Żmijewski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D018167:Receptors, Calcitriol / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics
chemical_list: C480634:20-hydroxyvitamin D3; D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014807:Vitamin D; C055085:calcipotriene; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol