Home Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines
Article
Licensed
Unlicensed Requires Authentication

Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines

  • Abeer Khriesha , Yasser Bustanji , Rana Abu Farha ORCID logo EMAIL logo , Reem Al-Abbasi and Bashaer Abu-Irmaileh
Published/Copyright: February 1, 2021
Become an author with De Gruyter Brill
Submit Manuscript Author Information
Hormone Molecular Biology and Clinical Investigation
From the journal Hormone Molecular Biology and Clinical Investigation Volume 42 Issue 1

Abstract

Objectives

Vitamin D is very important for calcium and mineral metabolism, and many hypotheses appear to link sunlight exposure with cancer risk and prognosis. As many studies supported the antitumor effect of vitamin D we wanted to investigate the potential effect of multiple vitamin D metabolites.

Methods

This study compared the anticancer effect of three inactive forms of vitamin D3 which are; cholecalciferol, alfacalcidol, and calcifediol on two human cancer cell lines colorectal cancer (CaCo II) and breast cancer (MCF-7). All were examined after 24, 48, and 72 h continuous exposure using a colorimetric assay (MTT) seeded in 96-multiwell plates. Doxorubicin anticancer used as a standard agent for comparison, while normal skin fibroblast cells (HDFa) was used as our negative control. IC50 values were calculated as indication of antitumor effect.

Results

Broad-spectrum of cytotoxicity with IC50 values ranging from 4 to 200 μM were found. Alfacalcidol was the most potent cytotoxic agents on colorectal cancer (CaCo II) and breast cancer (MCF-7) compared to cholecalciferol, and calcifediol. Both, alfacalcidol and calcifediol were more cytotoxic than cholecalciferol on the tested cell lines as they are partially active metabolites. Breast cancer (MCF-7) was the most sensitive to all metabolites at all-time intervals with the best IC50 values of 4.35 μM ± 1.06 after 72 h continuous exposure of alfacalcidol.

Conclusions

Vitamin D metabolites are a potential option for cancer treatment along with or an alternative to chemo-therapeutics although extensive preclinical studies are required to prove this effect.

Keywords: breast cancer; cell line; colorectal cancer; cytotoxic; vitamin D
Corresponding author: Rana Abu Farha, Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, PO. 11931Amman, Jordan, Phone: 0096265609957 ext 1496, Fax: 009625232899, E-mail:

Funding source: Deanship of Academic Research at the University of Jordan for Funding this Research

Award Identifier / Grant number: 2016

  1. Research funding: Authors would like to thank the Deanship of Academic Research at the University of Jordan for funding this research.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: None

  4. Informed consent: Not applicable.

  5. Ethical approval: The conducted research is not related to either human or animal use.

References

1. Li, H, Wang, X, Xu, G, Zeng, L, Cheng, K, Gao, P, et al.. Synthesis and biological evaluation of a novel class of coumarin derivatives. Bioorg Med Chem Lett 2014;24:5274–8. https://doi.org/10.1016/j.bmcl.2014.09.051.Search in Google Scholar

2. JMOH. The top ten cancer cases of Jordanians females and males. Epidemics; 2013. Available from: http://www.moh.gov.jo/Pages/viewpage.aspx?pageID=177 [Cited 24 Nov 2017].Search in Google Scholar

3. Bouillon, R, Okamura, WH, Norman, AW. Structure-function relationships in the vitamin D endocrine system. Endocr Rev 1995;16:200–57. https://doi.org/10.1210/edrv-16-2-200.Search in Google Scholar

4. Brockmann, H. Die Isolierung des antirachitischen Vitamins aus Thunfischleberöl. Hoppe-Seyler’s Z Physiol Chem 1936;241:104–15. https://doi.org/10.1515/bchm2.1936.241.1-3.104.Search in Google Scholar

5. Scl’lwartz, GG, Hulka, S. Is vitamin D deficiency a risk factor for prostate cancer?(Hypothesis). Anticancer Res 1990;10:807–1312.Search in Google Scholar

6. Vuolo, L, Di Somma, C, Faggiano, A, Colao, A. Vitamin D and cancer. Front Endocrinol 2012;3:58. https://doi.org/10.3389/fendo.2012.00058.Search in Google Scholar

7. Garland, CF, Garland, FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227–31. https://doi.org/10.1093/ije/9.3.227.Search in Google Scholar

8. Zerwekh, JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008;87:1087S–91S. https://doi.org/10.1093/ajcn/87.4.1087s.Search in Google Scholar

9. Jovičić, S, Ignjatović, S, Majkić-Singh, N. Biochemistry and metabolism of vitamin D/Biohemija i metabolizam vitamina D. J Med Biochem 2012;31:309–15.10.2478/v10011-012-0028-8Search in Google Scholar

10. Abrams, SA, Griffin, IJ, Hawthorne, KM, Gunn, SK, Gundberg, CM, Carpenter, TO. Relationships among vitamin D levels, parathyroid hormone, and calcium absorption in young adolescents. J Clin Endocrinol Metab 2005;90:5576–81. https://doi.org/10.1210/jc.2005-1021.Search in Google Scholar

11. Kulie, T, Groff, A, Redmer, J, Hounshell, J, Schrager, S. Vitamin D: an evidence-based review. J Am Board Fam Med 2009;22:698–706. https://doi.org/10.3122/jabfm.2009.06.090037.Search in Google Scholar

12. Christakos, S, Ajibade, DV, Dhawan, P, Fechner, AJ, Mady, LJ. Vitamin D: metabolism. Rheum Dis Clin N Am 2012;38:1–11. https://doi.org/10.1016/j.rdc.2012.03.003.Search in Google Scholar

13. Holick, MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. https://doi.org/10.1056/nejmra070553.Search in Google Scholar

14. Wranicz, J, Szostak-Wegierek, D. Health outcomes of vitamin D. Part I. Characteristics and classic role. Rocz Panstw Zakl Hig 2014;65:179–84.Search in Google Scholar

15. Anzano, MA, Smith, JM, Uskoković, MR, Peer, CW, Mullen, LT, Letterio, JJ, et al.. 1α,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer in the rat. Canc Res 1994;54:1653–6.Search in Google Scholar

16. Kennel, KA, Drake, MT, Hurley, DL. Vitamin D deficiency in adults: when to test and how to treat. in Mayo Clinic Proceedings. Elsevier; 2010, 85:752–7.10.4065/mcp.2010.0138Search in Google Scholar PubMed PubMed Central

17. Fraser, A, Williams, D, Lawlor, DA. Associations of serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001–2006). PloS One 2010;5:e13882. https://doi.org/10.1371/journal.pone.0013882.Search in Google Scholar

18. Wang, QM, Jones, JB, Studzinski, GP. Cyclin-dependent kinase inhibitor p27 as a mediator of the G1-S phase block induced by 1, 25-dihydroxyvitamin D3 in HL60 cells. Canc Res 1996;56:264–7.Search in Google Scholar

19. Bouillon, R, Eelen, G, Verlinden, L, Mathieu, C, Carmeliet, G, Verstuyf, A. Vitamin D and cancer. J Steroid Biochem Mol Biol 2006;102:156–62. https://doi.org/10.1016/j.jsbmb.2006.09.014.Search in Google Scholar

20. Krishnan, AV, Feldman, D. Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 2011;51:311–36. https://doi.org/10.1146/annurev-pharmtox-010510-100611.Search in Google Scholar

21. Lin, R, White, JH. The pleiotropic actions of vitamin D. Bioessays 2004;26:21–8. https://doi.org/10.1002/bies.10368.Search in Google Scholar

22. Skrajnowska, D, Bobrowska-Korczak, B. Potential molecular mechanisms of the anti-cancer activity of vitamin D. Anticancer Res 2019;39:3353–63. https://doi.org/10.21873/anticanres.13478.Search in Google Scholar

23. Giovannucci, E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 2005;16:83–95. https://doi.org/10.1007/s10552-004-1661-4.Search in Google Scholar

24. Schwartz, GG. Vitamin D and intervention trials in prostate cancer: from theory to therapy. Ann Epidemiol 2009;19:96–102. https://doi.org/10.1016/j.annepidem.2008.03.007.Search in Google Scholar

25. Grant, WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B Biol 2010;101:130–6. https://doi.org/10.1016/j.jphotobiol.2010.04.008.Search in Google Scholar

26. Baeke, F, van Etten, E, Gysemans, C, Overbergh, L, Mathieu, C. Vitamin D signaling in immune-mediated disorders: evolving insights and therapeutic opportunities. Mol Aspect Med 2008;29:376–87. https://doi.org/10.1016/j.mam.2008.05.004.Search in Google Scholar

27. Timerman, D, McEnery-Stonelake, M, Joyce, CJ, Nambudiri, VE, Stephen, FH, Claus, EB, et al.. Vitamin D deficiency is associated with a worse prognosis in metastatic melanoma. Oncotarget 2017;8:6873. https://doi.org/10.18632/oncotarget.14316.Search in Google Scholar

28. Keum, N, Lee, DH, Greenwood, DC, Manson, JE, Giovannucci, E. Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Ann Oncol 2019;30:733–43. https://doi.org/10.1093/annonc/mdz059.Search in Google Scholar

29. O’Brien, KM, Sandler, DP, Taylor, JA, Weinberg, CR. Serum vitamin D and risk of breast cancer within five years. Environ Health Perspect 2017;125:077004. https://doi.org/10.1289/EHP943.Search in Google Scholar

30. Zhang, Y, Jiang, X, Li, X, Găman, M-A, Kord-Varkaneh, H, Rahmani, J, et al.. Serum vitamin D levels and risk of liver cancer: a systematic review and dose-response meta-analysis of cohort studies. Nutrition and Cancer 2020:1–9. https://doi.org/10.1080/01635581.2020.1797127.Search in Google Scholar

31. Chung, M, Lee, J, Terasawa, T, Lau, J, Trikalinos, TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the US Preventive Services Task Force. Ann Intern Med 2011;155:827–38. https://doi.org/10.7326/0003-4819-155-12-201112200-00005.Search in Google Scholar

32. Ben-Eltriki, M, Deb, S, Guns, EST. Calcitriol in combination therapy for prostate cancer: pharmacokinetic and pharmacodynamic interactions. J Canc 2016;7:391. https://doi.org/10.7150/jca.13470.Search in Google Scholar

33. Da Violante, G, Zerrouk, N, Richard, I, Provot, G, Chaumeil, JC, Arnaud, P. Evaluation of the cytotoxicity effect of dimethyl sulfoxide (DMSO) on Caco2/TC7 colon tumor cell cultures. Biol Pharm Bull 2002;25:1600–3. https://doi.org/10.1248/bpb.25.1600.Search in Google Scholar

34. Mann, J. Natural products in cancer chemotherapy: past, present and future. Nat Rev Canc 2002;2:143–8. https://doi.org/10.1038/nrc723.Search in Google Scholar

35. van Poppel, G, van den Berg, H. Vitamins and cancer. Canc Lett 1997;114:195–202. https://doi.org/10.1016/s0304-3835(97)04662-4.Search in Google Scholar

36. Holick, MF, Chen, TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 2008;87:1080S–6S. https://doi.org/10.1093/ajcn/87.4.1080s.Search in Google Scholar

37. Wang, TJ, Pencina, MJ, Booth, SL, Jacques, PF, Ingelsson, E, Lanier, K, et al.. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503–11. https://doi.org/10.1161/circulationaha.107.706127.Search in Google Scholar

38. Hahn, TJ, Halstead, LR, Baran, DT. Effects of short term glucocorticoid administration on intestinal calcium absorption and circulating vitamin D metabolite concentrations in man. J Clin Endocrinol Metab 1981;52:111–5. https://doi.org/10.1210/jcem-52-1-111.Search in Google Scholar

39. Hershberger, PA, Yu, W-D, Modzelewski, RA, Rueger, RM, Johnson, CS, Trump, DL. Calcitriol (1, 25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Canc Res 2001;7:1043–51.Search in Google Scholar

40. Trump, DL, Muindi, J, Fakih, M, Yu, W-D, Johnson, CS. Vitamin D compounds: clinical development as cancer therapy and prevention agents. Anticancer Res 2006;26:2551–6.Search in Google Scholar

41. WHO. Estimated number of incident cases, both sexs, worldwild (top 10 cancer sites) in 2012. Incidence 2012 November, 24, 2017. Available from: http://gco.iarc.fr/today/online-analysis-pie?mode=cancer&mode_population=continents&population=900&sex=0&cancer=29&type=0&statistic=0&prevalence=0&color_palette=default [Accessed 24 Nov 2017].Search in Google Scholar

42. Carmichael, J, DeGraff, WG, Gazdar, AF, Minna, JD, Mitchell, JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Canc Res 1987;47:936–42.Search in Google Scholar

43. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63. https://doi.org/10.1016/0022-1759(83)90303-4.Search in Google Scholar

44. Giovannucci, E, Liu, Y, Rimm, EB, Hollis, BW, Fuchs, CS, Stampfer, MJ, et al.. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451–9. https://doi.org/10.1093/jnci/djj101.Search in Google Scholar

45. Davis, CD. Vitamin D and cancer: current dilemmas and future research needs. Am J Clin Nutr 2008;88:565S–9S. https://doi.org/10.1093/ajcn/88.2.565s.Search in Google Scholar

46. Kumagai, T, O’Kelly, J, Said, JW, Koeffler, HP. Vitamin D2 analog 19-nor-1, 25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma, and colon cancer cells. J Natl Cancer Inst 2003;95:896–905. https://doi.org/10.1093/jnci/95.12.896.Search in Google Scholar

47. Haddur, E, Ozkaya, AB, Ak, H, Aydin, HH. The effect of calcitriol on endoplasmic reticulum stress response. Biochem Cell Biol 2015;93:268–71. https://doi.org/10.1139/bcb-2014-0155.Search in Google Scholar

48. Gandini, S, Boniol, M, Haukka, J, Byrnes, G, Cox, B, Sneyd, MJ, et al.. Meta‐analysis of observational studies of serum 25‐hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Canc 2011;128:1414–24. https://doi.org/10.1002/ijc.25439.Search in Google Scholar

49. Bareis, P, Bises, G, Bischof, MG, Cross, HS, Peterlik, M. 25-hydroxy-vitamin D metabolism in human colon cancer cells during tumor progression. Biochem Biophys Res Commun 2001;285:1012–7. https://doi.org/10.1006/bbrc.2001.5289.Search in Google Scholar

50. Jeon, S-M, Shin, E-A. Exploring vitamin D metabolism and function in cancer. Exp Mol Med 2018;50:1–14. https://doi.org/10.1038/s12276-018-0038-9.Search in Google Scholar

51. Haussler, MR, Cordy, PE. Metabolites and analogues of vitamin D: which for what? J Am Med Assoc 1982;247:841–4. https://doi.org/10.1001/jama.1982.03320310085047.Search in Google Scholar

52. Barreto, SG, Neale, RE. Vitamin D and pancreatic cancer. Canc Lett 2015;368:1–6. https://doi.org/10.1016/j.canlet.2015.06.030.Search in Google Scholar

53. Shahvazi, S, Soltani, S, Ahmadi, SM, de Souza, RJ, Salehi-Abargouei, A. The effect of vitamin D supplementation on prostate cancer: a systematic review and meta-analysis of clinical trials. Horm Metab Res 2019;51:11–21. https://doi.org/10.1055/a-0774-8809.Search in Google Scholar

54. Afzali, M, Ghaeli, P, Khanavi, M, Parsa, M, Montazeri, H, Ghahremani, MH, et al.. Non-addictive opium alkaloids selectively induce apoptosis in cancer cells compared to normal cells. Daru 2015;23:16. https://doi.org/10.1186/s40199-015-0101-1.Search in Google Scholar

55. Al-Said, MS, Bashandy, MS, Al-qasoumi, SI, Ghorab, MM. Anti-breast cancer activity of some novel 1,2-dihydropyridine, thiophene and thiazole derivatives. Eur J Med Chem 2011;46:137–41. https://doi.org/10.1016/j.ejmech.2010.10.024.Search in Google Scholar

56. Ishii, S, Nagasawa, M, Kariya, Y, Yamamoto, H, Inouye, S, Kondo, S. Antitumor activity of pyrindamycins A and B. J Antibiot 1989;42:1713–7. https://doi.org/10.7164/antibiotics.42.1713.Search in Google Scholar

57. Kamal, A, Reddy, JS, Ramaiah, MJ, Dastagiri, D, Bharathi, E, Sagar, MVP, et al.. Design, synthesis and biological evaluation of imidazopyridine/pyrimidine-chalcone derivatives as potential anticancer agents. MedChemComm 2010;1:355–60. https://doi.org/10.1039/c0md00116c.Search in Google Scholar

58. Khalifa, MM, Ismail, MM, Noaman, E. Synthesis and in vitro cytotoxic activity of novel benzo [b] phenazine-6, 11-dione and 1, 4-naphthoquinone derivatives. Bull Pharmaceut Sci 2008;31:69–80.10.21608/bfsa.2008.64215Search in Google Scholar

59. Shah, SSA, Rivera, G, Ashfaq, M. Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoral, anti-bacterial and anti-inflammatory agents. Mini Rev Med Chem 2013;13:70–86. https://doi.org/10.2174/138955713804484749.Search in Google Scholar

Received: 2020-07-04
Accepted: 2021-01-14
Published Online: 2021-02-01

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Letter to the Editor
  3. Kerala model for combating COVID-19 pandemic
  4. Original Articles
  5. Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines
  6. Relationship between the levels of serum fibroblast growth factor 19 and metabolic factors in obese and normal weight subjects with and without type 2 diabetes mellitus: a case-control study
  7. Early-life stress altered pancreatic Krebs cycle-related enzyme activities in response to young adulthood physical and psychological stress in male rat offspring
  8. Effect of short-term and long-term traffic noise exposure on the thyroid gland in adult rats: a sexual dimorphic study
  9. The effect of thyroid dysfunction and treatment on adropin, asprosin and preptin levels in rats
  10. Comparison of the effects of zinc oxide and zinc oxide nanoparticles on the expression of hepcidin gene in rat liver
  11. Comparison between Iberet Folic® and Zincofer® in treatment of iron deficiency anaemia in pregnancy
  12. Mini Review
  13. COVID-19 and pregnancy: are they friends or enemies?
  14. Review Articles
  15. COVID-19: a review on SARS-CoV-2 origin, epidemiology, virology, clinical manifestations and complications with special emphasis on adverse outcome in Bhopal Gas Tragedy survivor
  16. COVID-19 and neurology perspective
  17. COVID-19 and nutritional deficiency: a review of existing knowledge
  18. COVID-19 and geriatric population: from pathophysiology to clinical perspectives
  19. COVID-19 and cardiovascular disease: a review of current knowledge
  20. How do different histologic components of mixed endometrial carcinomas affect prognosis? Does it really matter?
https://doi.org/10.1515/hmbci-2020-0045
Keywords for this article
breast cancer; cell line; colorectal cancer; cytotoxic; vitamin D

Articles in the same Issue

  1. Frontmatter
  2. Letter to the Editor
  3. Kerala model for combating COVID-19 pandemic
  4. Original Articles
  5. Evaluation of the potential anticancer activity of different vitamin D metabolites on colorectal and breast cancer cell lines
  6. Relationship between the levels of serum fibroblast growth factor 19 and metabolic factors in obese and normal weight subjects with and without type 2 diabetes mellitus: a case-control study
  7. Early-life stress altered pancreatic Krebs cycle-related enzyme activities in response to young adulthood physical and psychological stress in male rat offspring
  8. Effect of short-term and long-term traffic noise exposure on the thyroid gland in adult rats: a sexual dimorphic study
  9. The effect of thyroid dysfunction and treatment on adropin, asprosin and preptin levels in rats
  10. Comparison of the effects of zinc oxide and zinc oxide nanoparticles on the expression of hepcidin gene in rat liver
  11. Comparison between Iberet Folic® and Zincofer® in treatment of iron deficiency anaemia in pregnancy
  12. Mini Review
  13. COVID-19 and pregnancy: are they friends or enemies?
  14. Review Articles
  15. COVID-19: a review on SARS-CoV-2 origin, epidemiology, virology, clinical manifestations and complications with special emphasis on adverse outcome in Bhopal Gas Tragedy survivor
  16. COVID-19 and neurology perspective
  17. COVID-19 and nutritional deficiency: a review of existing knowledge
  18. COVID-19 and geriatric population: from pathophysiology to clinical perspectives
  19. COVID-19 and cardiovascular disease: a review of current knowledge
  20. How do different histologic components of mixed endometrial carcinomas affect prognosis? Does it really matter?
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 16.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hmbci-2020-0045/html
Scroll to top button