Koike M, Koshizuka K, Kawabata H, Yang R, Taub H E, Said J, Uskokovic M, Tsuruoka N, Koeffler H P
Division of Hematology/Oncology, UCLA School of Medicine, USA.
Anticancer Res. 1999 May-Jun;19(3A):1689-97.
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.
我们合成并研究了一系列九种新型1,25-二羟基维生素D3[1,25(OH)2D3]类似物抑制髓系白血病细胞(HL-60)、前列腺癌(LNCaP、PC-3和DU-145)及乳腺癌(MCF-7)癌细胞克隆生长的能力。DU-145细胞对所有这些修饰的化合物均具有活性抗性，但当我们去除C-19（E,1,25-二羟基-23E-烯-26,27-六氟-19-去甲-20-环丙基胆钙化醇）后，得到了一种对所有三种前列腺癌细胞系、乳腺癌细胞系及HL-60细胞系均有抑制作用的类似物。进一步分析表明，用该类似物脉冲处理（3天，10(-7)M）足以使PC-3细胞的克隆生长抑制50%。此外，化合物E增加了G1期PC-3细胞的数量，减少了S期细胞数量。1,25(OH)2D3通过与维生素D3受体(VDR)特异性结合并随后与1,25(OH)2D3调节的基因中的维生素D3反应元件(VDRE)结合来介导其生物学活性。最近已鉴定出几种新型维生素D3化合物，与亲本1,25(OH)2D3相比，它们诱导前列腺癌、乳腺癌和HL-60白血病原始细胞分化及抑制其增殖的能力强5至1000倍。为阐明这些维生素D3类似物中的九种介导其显著强效生物学活性的机制，我们研究了它们在PC-3前列腺癌细胞中激活含有人骨钙素基因的VDRE与胸苷激酶最小启动子相连的氯霉素乙酰转移酶(CAT)报告基因的能力。化合物E的剂量反应研究表明，在无血清培养条件下，VDRE-CAT的激活比化合物J[1,25(OH)2D3]更强。然后，我们研究了维生素D3化合物J对小鼠的影响。我们的数据表明，就小鼠的肿瘤大小和肿瘤重量而言，维生素D3化合物E在前列腺癌细胞系(PC-3)中的生长抑制作用在统计学上优于未治疗组。总之，这是关于一系列具有抑制LNCaP、PC-3、DU-145、MCF-7和HL-60细胞系增殖能力的强效20-环丙基胆钙化醇维生素D3类似物的首次报道。这些化合物可能通过细胞周期阻滞途径介导其强效抗增殖活性。
