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

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.

• Authors: S R Evans, V Soldatenkov, E B Shchepotin, E Bogrash, I B Shchepotin
• Journal: International journal of oncology (Int J Oncol) Vol. 14 Issue 5 Pg. 979-85 (May 1999) ISSN: 1019-6439 [Print] Greece
• PMID: 10200351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Calcitriol (pharmacology)
• Cell Division (drug effects)
• Cholecalciferol (analogs & derivatives, 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