Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells.

Abstract

BACKGROUND:

1,25 dihydroxyvitamin D3 (1,25D) and retinoids may play an important role in preventing progression of prostate cancer.

METHODS:

We examined the ability of four novel 20-epi-vitamin D3 analogs (CB1093, KH1060, KH1266, and CB1267), either alone or in combination with 9-cis retinoic acid (RA) to inhibit colony growth of a human prostate cancer cell line, LNCaP, using soft agar as well as bone marrow stroma. Also, the effect of these analogs on the cell cycle and expression of Ki-67, p21(waf-1), and p27(kip1) in LNCaP cells was examined.

RESULTS:

The analog CB1267 was the most potent, with 8 x 10(-10) M of the analog inhibiting 50% colony growth (ED50) of LNCaP. 9-cis-RA also inhibited colony growth of LNCaP (ED50, 5 x 10(-7) M). Combined, CB1267 and 9-cis-RA synergistically inhibited colony growth and significantly increased the number of LNCaP cells in G0/G1 phase. Cell cycle arrest was associated with increased levels of p21(waf-1) and p27(kip1) and decreased expression of Ki-67 protein. Pulse-exposure to this combination (5 x 10(-8) M) irreversibly inhibited colony growth, both in soft agar and on normal human bone marrow stroma.

CONCLUSIONS:

Combination of a new vitamin D3 analog (CB1267) and a retinoid (9-cis-RA) potently inhibited colony formation of LNCaP prostate cancer cells in vitro, suggesting further studies in animal models. This combination may afford an interesting therapeutic approach to low-burden prostate cancer.

• Authors: E Elstner, M J Campbell, R Munker, P Shintaku, L Binderup, D Heber, J Said, H P Koeffler
• Journal: The Prostate (Prostate) Vol. 40 Issue 3 Pg. 141-9 (Aug 01 1999) ISSN: 0270-4137 [Print] United States
• PMID: 10398275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 1999 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents
• CB 1093
• CB 1267
• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• KH 1266
• Microtubule-Associated Proteins
• Tumor Suppressor Proteins
• KH 1060
• Cyclin-Dependent Kinase Inhibitor p27
• Alitretinoin
• Tretinoin
• Calcitriol

Topics

• Alitretinoin
• Antineoplastic Agents (toxicity)
• Bone Marrow Cells (cytology)
• Calcitriol (analogs & derivatives, toxicity)
• Cell Cycle (drug effects)
• Cell Cycle Proteins
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclins (metabolism)
• Drug Synergism
• Humans
• Male
• Microtubule-Associated Proteins (metabolism)
• Prostatic Neoplasms
• Stromal Cells (cytology, drug effects)
• Tretinoin (toxicity)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins