Novel 19-nor-hexafluoride vitamin D3 analog (Ro 25-6760) inhibits human colon cancer in vitro via apoptosis

Int J Oncol. 1999 May;14(5):979-85. doi: 10.3892/ijo.14.5.979.

Abstract

Our previously performed experiments clearly showed a significant VDR-mediated growth inhibitory effect of 1,25-dihydroxyvitamin D3 and its synthetic analogs in a variety of human cancer cells including human colon and breast cancer, soft tissue sarcoma, and malignant melanoma cell lines. The mechanisms by which 1, 25-dihydroxyvitamin D3 and its synthetic analogs growth inhibit human cancer cells is poorly elucidated. The exposure of human colon cancer cells HT-29 to 1,25-dihydroxyvitamin D3 or its analog, 1alpha, 25-dihydroxy-16-ene-23yne-26,27-hexafluoro-19-nor-choleca lci ferol (Ro 25-6760), at the 10(-6) M concentration resulted in significant growth inhibition with induction of the apoptotic process after three days of treatment detected by TUNEL assay and agarose gel electrophoresis of DNA. As a logical link with DNA fragmentation analyses and TUNEL assay, cleavage of the 116 kDa PARP protein was accompanied by the appearance of a characteristic 85 kDa fragment of PARP in a population of floating cells after both treatments. The results of cell cycle analysis showed a G0/G1 phase block after three days of administration of either compound when compared with untreated cells. On day 4, G0/G1 cell cycle arrest remained on the same level in comparison with control. Paralleling the G0/G1 phase block, was a notable decrease in the number of cells in the S phase which also became significant after three days of treatment. The results of these experiments show that the newly developed 19-nor synthetic vitamin D3 analog, Ro 25-6760, as well as 1, 25-dihydroxyvitamin D3, induced the expression of p21waf1, resulted in a significant G1/G0 cell cycle arrest leading to impressive growth inhibition and induction of apoptosis associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) showing a possible involvement of apoptosis-specific activation of the ICE/CED-3 proteolitic pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis*
  • Calcitriol / pharmacology
  • Cell Division / drug effects
  • Cholecalciferol / analogs & derivatives*
  • Cholecalciferol / pharmacology
  • Colonic Neoplasms / pathology*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / metabolism
  • G1 Phase / drug effects
  • HT29 Cells
  • Humans
  • Peptide Hydrolases / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Resting Phase, Cell Cycle / drug effects
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Ro 25-6760
  • Cholecalciferol
  • Poly(ADP-ribose) Polymerases
  • Peptide Hydrolases
  • Calcitriol