Biological effects of 1α-hydroxy- and 1β-(hydroxymethyl)-vitamin D compounds relevant for potential colorectal cancer therapy

Harald Hofer, Guan Min Ho, Meinrad Peterlik, Milan R. Uskokovic, Jae Kyoo Lee, M. Christina White, Gary H. Posner, Heide S. Cross

Research output: Contribution to journalArticle

Abstract

1α,25-Dihydroxyvitamin D3 and two synthetic analogs, 1α,25-dihydroxy- 16-ene-23-yne-vitamin D3 (Ro 23-7553) and 1α,25-dihydroxy-16-ene-24-oxo- vitamin D3 (JK-1624-3), were tested for their ability to specifically inhibit growth and promote differentiation of human colon cancer cells in comparison with a series of 1β-(hydroxymethyl) congeners of the natural hormone, such as 1β-(hydroxymethyl)-3α,25(OH)2-16-ene,24-oxo-vitamin D3 (JK-1624-2), 1β-(hydroxymethyl)-3α,25-dihydroxy-16-ene-26,27-dihomo vitamin D3 (JK-1626-2), and 1β-(hydroxymethyl)-3α,25-dihydroxy-22,24-diene-26,27- dihomo vitamin D3 (MCW-EE). Western blot analysis revealed that reduction of cyclin D1 levels is a key mechanism by which the vitamin D compounds under investigation inhibit Caco-2 tumor cell growth. Both the 1α-hydroxy- as well as the 1β-hydroxymethyl-type vitamin D compounds, which exhibit only low affinity for the vitamin D receptor, significantly reduced [3H]thymidine DNA labeling in confluent Caco-2 cell cultures. This suggests that high-affinity binding to the vitamin D receptor is not an absolute prerequisite for genomic action on tumor cell growth. Hybrid analogs JK-1624-2 and MCW-EE, although antimitotically active, were rather ineffective in promoting phenotypic differentiation of human colon cancer cells. However, because both compounds also do not promote osteoclast differentiation from hematopoetic bone marrow cells, they still could be used as antimitotic agents in cancer therapy, even at dose levels that, with other analogs, could cause hypercalcemia.

Original languageEnglish (US)
Pages (from-to)450-455
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume291
Issue number2
StatePublished - Nov 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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