Mechanism of action +

Identified for its major role in regulating calcium absorption from the gut, storage in mineral form in the bones, and excretion by the kidneys, vitamin D can influence the regulation of a very broad range of biological functions linked with cell proliferation, cell differentiation, cell death, inflammation or immune reactions. Therefore, vitamin D's role has been investigated in multiple diseases.

As shown in the figure below, calcitriol (1,25(OH)2D3- the active form of vitamin D) circulates in the body bound to the vitamin D binding protein which protects it from degradation. When it dissociates from the vitamin D binding protein and enters into the cell, calcitriol binds to the vitamin D receptor (VDR) which then links to the retinoid X receptor (RXR). This calcitriol/VDR/RXR complex then binds to specific DNA sequences called vitamin D response elements (VDRE) to induce or repress expression of target genes. VDRE-regulated genes are involved in a wide variety of biological functions (calcium homeostasis, cell proliferation or apoptosis, cell differentiation, inflammation and immunomodulation…).

Reproduit de Davis and Milner: J Nutrigenet Nutrigenomics 2011;4:1–11

Inecalcitol also acts by binding to the vitamin D receptor but some of its properties differ from calcitriol's. Inecalcitol does not bind to the vitamin D binding protein which means that it readily penetrates into cells without accumulating in the bloodstream, allowing it to have a more manageable half-life. Inecalcitol's binding to VDR is performed in a different conformation to that of calcitriol, which leads to an inecalcitol/VDR/RXR complex that not bind to the same VDREs or binds with different affinities than those of calcitriol's complex. The genes up- or down-regulated following inecalcitol binding are therefore different. For example, inecalcitol has been shown to repress cyclin D1 and cyclin C gene expression and to induce p21 and p27 gene expression more efficiently than calcitriol ; all four genes are involved in cell cycle progression.

Prostate cancer +

Clinical results

A Phase IIa study of inecalcitol, in 54 castrate-resistant prostate cancer (CRPC) patients, was run in five centers in France and led by the medical oncology department at the Georges Pompidou Hospital in Paris. The study was designed to determine the maximum tolerated dose (MTD) of inecalcitol in combination with the standard of care, Taxotere® (docetaxel).

While demonstrating excellent safety, inecalcitol, administrated in addition to Taxotere®, also showed a highly promising efficacy signals with 85% of the patients showing a PSA (Prostate Specific Antigen – a marker of disease likelihood, also used as a marker of response to therapy) decline of at least 30% during the first 3 months of therapy. This compares very favorably to Taxotere® alone as the main registration trial for Taxotere® demonstrated a greater than 30% reduction in PSA scores over the same timeframe in 67% of patients tested. Moreover, this observed response rate was also greater than published rates for other drugs in development with Taxotere®for CRPC.

Disease description

Prostate cancer is a slow-growing cancer which can be treated surgically if identified early enough. Unfortunately, it can quickly spread beyond the prostate gland before it is properly diagnosed, then requiring lengthy therapy following surgery. With 520,000 new prostate cancer cases diagnosed in 2011 in the United States, France, Germany, Italy, Spain, United Kingdom and Japan, prostate cancer is the most common cancer in men and is the second cause of death from cancer after lung cancer. The treatment modality usually includes hormonal therapy which is effective in 80% of cases however, it does not cure the cancer, it just stops it from spreading. In 20% of the cases, the cancer will grow again despite the hormonal therapy, it is then designated as “castrate-resistant prostate cancer” and will require chemotherapy-based treatment.

Useful links

Chronic Lymphocytic Leukemia +

Clinical results

Vitamin D's beneficial effect of on the progression of chronic lymphocytic leukemia (CLL) was established very recently. Epidemiological studies have revealed the CLL patients suffering from vitamin D deficiency were twice as likely to die within 3 years of diagnosis compared to patients with normal vitamin D levels. Another study also showed that oral administration of vitamin D by a CLL patient could strongly decrease their blood leukemia lymphocyte count.

A clinical study is ongoing to determine Inecalcitol's efficacy in the treatment of CLL.

Disease description

CLL is the most frequent form of leukemia (cancerous proliferative disease of circulating blood cells) and accounts for about 35% of all leukemic patients. Annual estimates of newly diagnosed CLL cases amount to close to 130,000 world-wide (Globocan 2008).

CLL patients make too many lymphocytes (mononuclear white blood cells) of one single abnormal “family” (monoclonal) which are not fully developed (immature). Over time, these circulating lymphocytes build up in the lymphatic system and cause large, swollen lymph nodes. They may also fill the bone marrow, reducing the number of normal white cells, red cells and platelets that can be made, thereby lowering their blood counts. CLL cannot usually be cured, therapy is used to slow its progression and manage symptoms. CLL is designated as an orphan disease in the United States, Europe and Japan.


Useful links

Literature references +


This section focuses on papers describing inecalcitol, also known as TX522.

  • Ma Y, Yu WD, Hidalgo AA, Luo W, Delansorne R, Johnson CS, Trump DL. Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. Cell Cycle. 2013 March 1. PMID: 23388458
  • Okamoto R, Delansorne R, Wakimoto N, Doan NB, Akagi T, Shen M, Ho QH, Said JW, Phillip Koeffler H. Inecalcitol, an analog of 1α,25(OH)(2) D(3) , induces growth arrest of androgen-dependent prostate cancer cells. Int J Cancer. 2011 Jul 5. PMID:21732345
  • Eelen G, Verlinden L, Rochel N, Claessens F, De Clercq P, Vandewalle M, Tocchini-Valentini G, Moras D, Bouillon R, Verstuyf A. Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction. Mol Pharmacol. 2005 May;67(5):1566-73. Epub 2005 Feb 22. PMID:15728261
  • Verlinden L, Verstuyf A, Quack M, Van Camp M, Van Etten E, De Clercq P, Vandewalle M, Carlberg C, Bouillon R. Interaction of two novel 14-epivitamin D3 analogs with vitamin D3 receptor-retinoid X receptor heterodimers on vitamin D3 responsive elements. J Bone Miner Res. 2001 Apr;16(4):625-38. PMID: 11315990
  • Verlinden L, Verstuyf A, Van Camp M, Marcelis S, Sabbe K, Zhao XY, De Clercq P, Vandewalle M, Bouillon R. Two novel 14-Epi-analogues of 1,25-dihydroxyvitamin D3 inhibit the growth of human breast cancer cells in vitro and in vivo. Cancer Res. 2000 May 15;60(10):2673-9. PMID:10825140

Vitamin D

This section highlights a selection of recent papers describing vitamin D and its role in cancer or other diseases.

  • Shanafelt TD, Drake MT, Maurer MJ, Allmer C, Rabe KG, Slager SL, Weiner GJ, Call TG, Link BK, Zent CS, Kay NE, Hanson CA, Witzig TE, Cerhan JR. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood. 2011 Feb 3;117(5):1492-8. Epub 2010 Nov 3.PMID:21048153
  • Davis CD, Milner JA. Nutrigenomics, vitamin D and cancer prevention. J Nutrigenet Nutrigenomics. 2011;4(1):1-11. Epub 2011 Mar 23. PMID:21430387.
  • Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010 Dec;9(12):941-55. Review. PMID:21119732
  • Gocek E, Studzinski GP. Vitamin D and differentiation in cancer. Crit Rev Clin Lab Sci. 2009;46(4):190-209. Review. PMID:19650715