Investigational New Drugs

, Volume 31, Issue 2, pp 247–255 | Cite as

Inhibition of cancer growth and induction of apoptosis by BGP-13 and BGP-15, new calcipotriene-derived vitamin D3 analogs, in-vitro and in-vivo studies

  • Amnon C. Sintov
  • Liron Berkovich
  • Shimon Ben-ShabatEmail author


One of the most innovative approaches to the treatment of cancer entails the use of 1α,25-dihydroxyvitamin D3 (calcitriol) analogs to inhibit cancer cell growth. We demonstrate here that BGP-13, a new calcipotriene-based 1α,25-dihydroxyvitamin D3 analog that we synthesized in our laboratory, inhibits the growth of prostate cancer (LNCaP), breast cancer (MCF-7), and colon cancer (HT-29) cell lines. Moreover, we also show that BGP-13 causes cells both to accumulate in G0-G1 and to activate caspase-3 and undergo apoptosis. In addition, we observed elevated vitamin D receptor (VDR) mRNA and protein levels in both LNCaP and MCF-7 cells following the exposure of the two cell lines to BGP-13. Importantly, we found that both the new analog BGP-13 and also BGP-15, another calcipotriene-based analog we synthesized previously and about which we published recently, inhibit the growth of HT-29 tumor xenografts in nude mice.


Calcipotriene Vitamin D3 Vitamin D receptor Apoptosis Tumor xenografts 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83(6):835–839PubMedCrossRefGoogle Scholar
  2. 2.
    Brown AJ, Dusso A, Slatopolsky E (1999) Vitamin D. Am J Physiol 277:F157–F175PubMedGoogle Scholar
  3. 3.
    Deeb KK, Trump DL, Johnson CS (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7:684–700PubMedCrossRefGoogle Scholar
  4. 4.
    Beer TM, Myrthue A (2004) Calcitriol in cancer treatment: from the lab to the clinic. Mol Cancer Ther 3:373–381PubMedGoogle Scholar
  5. 5.
    Zhuang SH, Burnstein KL (1998) Antiproliferative effect of 1alpha,25-dihydroxyvitamin D3 in human prostate cancer cell line LNCaP involves reduction of cyclin-dependent kinase 2 activity and persistent G1 accumulation. Endocrinology 139:1197–1207PubMedCrossRefGoogle Scholar
  6. 6.
    Guzey M, Kitada S, Reed JC (2002) Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer. Mol Cancer Ther 1:667–677PubMedGoogle Scholar
  7. 7.
    Hansen CM, Frandsen TL, Brünner N, Binderup L (1994) 1 alpha,25-Dihydroxyvitamin D3 inhibits the invasive potential of human breast cancer cells in vitro. Clin Exp Metastasis 12:195–202PubMedCrossRefGoogle Scholar
  8. 8.
    Young MR, Ihm J, Lozano Y, Wright MA, Prechel MM (1995) Treating tumor-bearing mice with vitamin D3 diminishes tumor-induced myelopoiesis and associated immunosuppression, and reduces tumor metastasis and recurrence. Cancer Immunol Immunother 41:37–45PubMedGoogle Scholar
  9. 9.
    Schwartz GG, Wang MH, Zang M, Singh RK, Siegal GP (1997) 1 alpha,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. Cancer Epidemiol Biomarkers Prev 6:727–732PubMedGoogle Scholar
  10. 10.
    Trump DL, Hershberger PA, Bernardi RJ, Ahmed S, Muindi J, Fakih M, Yu WD, Johnson CS (2004) Anti-tumor activity of calcitriol: pre-clinical and clinical studies. J Steroid Biochem Mol Biol 89–90:519–526PubMedCrossRefGoogle Scholar
  11. 11.
    James SY, Mackay AG, Colston KW (1996) Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol 58:395–401PubMedCrossRefGoogle Scholar
  12. 12.
    Lokeshwar BL, Schwartz GG, Selzer MG, Burnstein KL, Zhuang SH, Block NL, Binderup L (1999) Inhibition of prostate cancer metastasis in vivo: a comparison of 1,23-dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiol Biomarkers Prev 8:241–248PubMedGoogle Scholar
  13. 13.
    Carlberg C (2004) Ligand-mediated conformational changes of the VDR are required for gene transactivation. J Steroid Biochem Mol Biol 89–90:227–232PubMedCrossRefGoogle Scholar
  14. 14.
    Wietrzyk J, Chodyński M, Fitak H, Wojdat E, Kutner A, Opolski A (2007) Antitumor properties of diastereomeric and geometric analogs of vitamin D3. Anticancer Drugs 18:447–457PubMedCrossRefGoogle Scholar
  15. 15.
    Berger U, Wilson P, McClelland RA, Colston K, Haussler MR, Pike JW, Coombes RC (1988) Immunocytochemical detection of 1,25-dihydroxyvitamin D receptors in normal human tissues. J Clin Endocrinol Metab 67:607–613PubMedCrossRefGoogle Scholar
  16. 16.
    Hussain-Hakimjee EA, Mehta RG (2009) Regulation of steroid receptor expression by 1alpha-hydroxyvitamin D3 in hormone-responsive breast cancer cells. Anticancer Res 29:3555–3561PubMedGoogle Scholar
  17. 17.
    Wiese RJ, Uhland-Smith A, Ross TK, Prahl JM, DeLuca HF (1992) Up-regulation of the vitamin D receptor in response to 1,25-dihydroxyvitamin D3 results from ligand-induced stabilization. J Biol Chem 267:20082–20086PubMedGoogle Scholar
  18. 18.
    Reichrath J, Müller SM, Kerber A, Baum HP, Bahmer FA (1997) Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. J Am Acad Dermatol 36:19–28PubMedCrossRefGoogle Scholar
  19. 19.
    Chung I, Han G, Seshadri M, Gillard BM, Yu WD, Foster BA, Trump DL, Johnson CS (2009) Role of Vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo. Cancer Res 69:967–975PubMedCrossRefGoogle Scholar
  20. 20.
    Van de Kerkhof PC (1998) An update on vitamin D3 analogues in the treatment of psoriasis. Skin Pharmacol Appl Skin Physiol 11:2–10PubMedCrossRefGoogle Scholar
  21. 21.
    Luba KM, Stulberg DL (2006) Chronic plaque psoriasis. Am Fam Physician 73:636–644PubMedGoogle Scholar
  22. 22.
    Takahashi H, Ibe M, Kinouchi M, Ishida-Yamamoto A, Hashimoto Y, Iizuka H (2003) Similarly potent action of 1,25-dihydroxyvitamin D3 and its analogues, tacalcitol, calcipotriol, and maxacalcitol, on normal human keratinocyte proliferation and differentiation. J Dermatol Sci 31:21–28PubMedCrossRefGoogle Scholar
  23. 23.
    Binderup L, Bramm E (1988) Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 37:889–895PubMedCrossRefGoogle Scholar
  24. 24.
    Berkovich L, Ben-Shabat S, Sintov AC (2010) Induction of apoptosis and inhibition of prostate and breast cancer growth by BGP-15, a new calcipotriene-derived vitamin D3 analog. Anticancer Drugs 21(6):609–618PubMedCrossRefGoogle Scholar
  25. 25.
    Adam W, Saha-Möller RC, Simon BS (1999) A Highly Diastereoselective Dioxetane Formation by the Hydroxy-Directed [2+2] Cycloaddition of Singlet Oxygen to a Chiral Allylic Alcohol. J Am Chem Soc 121(9):1834–1838CrossRefGoogle Scholar
  26. 26.
    Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4(8):592–603PubMedCrossRefGoogle Scholar
  27. 27.
    Adam W, Prein M (1996) pi-Facial diastereoselectivity in the [4+2] cycloaddition of singlet oxygen as a mechanistic probe. Accounts of chemical research 29:275–283CrossRefGoogle Scholar
  28. 28.
    Ben-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Nakanishi N, Turro NJ (2002) A nona-oxirane formation from A2E, a lipofuscin flurophore related to macular degeneration and evidence of singlet oxygen involvement. Angew Chem Int Ed Engl 41:814–817PubMedCrossRefGoogle Scholar
  29. 29.
    Chambers TJ, Serafini EP (1985) The permeability of normal, adenomatous, ulcerative colitic and malignant large bowl epithelial cell membranes to inulin. Br J Exp Path 66:309–315Google Scholar
  30. 30.
    Picardo M, Passi S, Sirianni C, Fiorilli M, Russo DG, Cortesi E, Barile G, Breathnach AS, Nazzaro-Porro M (1985) Activity of azelaic acid on cultures of lymphoma- and leukemia-derived cell lines, normal resting and stimulated lymphocytes and 3T3 fibroblasts. Biochem Pharmacol 34:1653–1658PubMedCrossRefGoogle Scholar
  31. 31.
    Masuda S, Strugnell S, Calverley MJ, Makin HL, Kremer R, Jones G (1994) In vitro metabolism of the anti-psoriatic vitamin D analog, calcipotriol, in two cultured human keratinocyte models. J Biol Chem 269(7):4794–4803PubMedGoogle Scholar
  32. 32.
    Hewison M (2011) Vitamin D and innate and adaptive immunity. Vitam Horm 86:23–62PubMedCrossRefGoogle Scholar
  33. 33.
    Wang Y, Zhu J, Deluca HF (2012) Where is the vitamin D receptor? Arch Biochem Biophys. 2012 Apr 6. [Epub ahead of print]Google Scholar
  34. 34.
    Kasibhatla S, Tseng B (2003) Why target apoptosis in cancer treatment? Mol Cancer Ther 2:573–580PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Amnon C. Sintov
    • 2
  • Liron Berkovich
    • 1
  • Shimon Ben-Shabat
    • 1
    Email author
  1. 1.Department of Pharmacology, Faculty of Health SciencesBen-Gurion University of the NegevBeer-ShevaIsrael
  2. 2.Department of Biomedical Engineering, Faculty of Engineering SciencesBen-Gurion University of the NegevBeer-ShevaIsrael

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