Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer
Evaluation of C-2-substituted 19-nor-1α,25-dihydroxyvitamin D3 analogs as therapeutic agents for prostate cancer
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DOI：
10.1016/j.jsbmb.2006.12.009
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发表时间：
2007-03-01
影响因子：
4.1
通讯作者：
Kittaka, A.
中科院分区：
文献类型：
--
作者：
Chen, T. C.;Persons, K. S.;Kittaka, A.
已知1 α，25-二羟基维生素D-3 (1 α,25（OH)(2)D-3）可抑制前列腺癌细胞的增殖和侵袭性。然而，la,25(OH)2D3可引起高钙血症，不适合作为治疗剂。19 .非维生素D衍生物在系统使用时，已知钙化程度较低。为了开发更有效的抗癌药物，减少钙化副作用，我们利用h -3胸腺嘧啶结合作为细胞增殖的指标，并检测了9种c -2取代的19-no -1 α，25(OH)(2)D-3类似物在永生化PZ-HPV-7正常前列腺细胞系中的抗增殖活性。在9个类似物中，我们观察到2 α -或2 β -羟丙基取代产生的两种类似物具有抗增殖效力，比1 α，25(OH)(2)D-3高约500至1000倍。细胞经1 α、25(OH)(2)D-3、19-nor-2 α -（3-羟丙基）-1 α、25(OH)(2)D-3或19-nor-2 β -（3-羟丙基）-1 α、25(OH)(2)D-3处理7天后，细胞计数数据支持h -3-胸苷苷掺入数据。在前列腺癌细胞的细胞侵袭研究中，19-no -2 α -（3-羟丙基）-1 α,25(OH)(2)D-3和19-no -2 β -（3-羟丙基）-1 α,25(OH)(2)D-3的活性也比1 α，25(OH)(2)D-3高约10倍。综上所述，在19-no -1 α，25(OH)(2)D-3分子的C-2位置上用羟基丙基取代可显著提高其抗增殖和抗侵袭能力。因此，这两种类似物可以开发为治疗早期和晚期前列腺癌的有效药物。(c) 2006 Elsevier Ltd.版权所有。
1 alpha,25-Dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, la,25(OH)2D3 can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Nor-vitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized H-3-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of nine C-2-substituted 19-nor-1 alpha,25(OH)(2)D-3 analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the nine analogs we observed that the substitution with 2 alpha- or 2 beta-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than 1 alpha,25(OH)(2)D-3. The H-3-thymidine incorporation data were supported by the cell counting data after cells were treated with 1 alpha,25(OH)(2)D-3, 19-nor-2 alpha-(3-hydroxypropyl)-1 alpha,25(OH)(2)D-3 or 19-nor-2 beta-(3-hydroxypropyl)-1 alpha,25(OH)(2)D-3 for 7 days. 19-Nor-2 alpha-(3-hydroxypropyl)-1 alpha,25(OH)(2)D-3 and 19-nor-2 beta-(3-hydroxypropyl)-1 alpha,25(OH)(2)D-3 were also shown to be about 10-fold more active than 1 alpha,25(OH)(2)D-3 in cell invasion studies using prostate cancer cells. In conclusion, a substitution at the C-2 position of 19-nor-1 alpha,25(OH)(2)D-3 molecule with a hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer. (c) 2006 Elsevier Ltd. All rights reserved.