Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells.
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.
Division of Hematology-Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA.
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E
Elstner
M J
MJ
Campbell
R
R
Munker
P
P
Shintaku
L
L
Binderup
D
D
Heber
J
J
Said
H P
HP
Koeffler
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000166:cytology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D014212:Tretinoin / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; C103436:CB 1093; C120580:CB 1267; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C103921:KH 1266; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; C074279:KH 1060; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077556:Alitretinoin; D014212:Tretinoin; D002117:Calcitriol