20-Cyclopropyl-cholecalciferol vitamin D3 analogs: a unique class of potent inhibitors of proliferation of human prostate, breast and myeloid leukemia cell lines.
We have synthesized and studied the ability of a series of nine novel 1,25 dihydroxyvitamin D3 [1,25(OH)2D3] analogs to inhibit clonal growth of myeloid leukemic cells (HL,60), prostate (LNCaP, PC-3 and DU-145) and breast (MCF-7) cancers cells. DU-145 cells were actively resistant to compounds (cmpd) with all of these modifications, but when we removed C-19 (E, 1,25-Dihydroxy-23E-ene-26,27-hexafluoro-19-nor-20-cyclopropy l- cholecalciferol) an analog resulted that was inhibitory against all three prostate cell lines, breast and HL-60 cell lines. Further analysis showed that pulse exposure (3 days, 10(-7) M) to this analog was enough to inhibit clonal growth of PC-3 cell by 50%. Furthermore, cmpd E increased the number of PC-3 cells in G1 and decreased the number in S phase. 1,25(OH)2D3 mediates its biological activities through specific binding to the vitamin D3 receptor (VDR) and subsequent association with vitamin D3 response elements (VDRE) in genes modulated by 1,25(OH)2D3. Several novel vitamin D3 cmpds have recently been identified which have 5- to 1000-fold greater abilities to induce differentiation and to inhibit proliferation of prostate cancer, breast cancer and HL-60 leukemic blast cells as compared to the parental 1,25(OH)2D3. To clarify the mechanism by which nine of these vitamin D3 analogs mediate their remarkably potent biological activities, we have investigated their abilities in PC-3 prostate cancer cells to transactivate a chroramphenicol acetyl transferase (CAT) reporter gene containing a VDRE from the human osteocalcin gene attached to a thymidine kinase minimal promoter. Dose-response studies of Cmpd E showed that in serumless culture conditions, transactivation of the VDRE-CAT was stronger than cmpd J [1,25(OH)2D3]. Then, we investigated the effects of vitamin D3 cmpd J in mice. Our data showed the growth inhibitory action of the vitamin D3 cmpd E in prostate cancer cell line (PC-3) was stastically superior to the non-treatment group in terms of tumor size and tumor weight in mice. In summary, this is the first report of a potent series of 20-cyclopropyl-cholecalciferol vitamin D3 analogs with the ability to inhibit proliferation of LNCaP, PC-3, DU-145, MCF-7 and HL-60 cell lines. These cmpds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.
Koike
M
M
Division of Hematology/Oncology, UCLA School of Medicine, USA.
Koshizuka
K
K
Kawabata
H
H
Yang
R
R
Taub
H E
HE
Said
J
J
Uskokovic
M
M
Tsuruoka
N
N
Koeffler
H P
HP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced / Q000517:prevention & control; D007951:Leukemia, Myeloid / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002762:Cholecalciferol