Flanagan John N, Zheng Shasha, Chiang Kun-Chun, Kittaka Atsushi, Sakaki Toshiyuki, Nakabayashi Sachie, Zhao Xiansi, Spanjaard Remco A, Persons Kelly S, Mathieu Jeffrey S, Holick Michael F, Chen Tai C
Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Anticancer Res. 2009 Sep;29(9):3547-53.
The high incidence of prostate cancer and lack of an effective, long-term treatment for metastatic disease highlights the need for more potent non-calcemic vitamin D analogs as potential alternative or combinational prostate cancer therapies. Among the analogs, 19-nor-1alpha,25-dihydroxyvitamin D2 (19-nor-1alpha,25(OH)2D2) known as paricalcitol or Zempler, has less calcemic effects and an equipotential activity as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) in several in vivo and in vitro systems. It was recently demonstrated that a modified analog of paricalcitol, 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 (MART-10) compared to 1alpha,25(OH)2D3 was more effective in inhibiting proliferation of an immortalized normal prostate cell line (PZ-HPV-7) (1,000-fold) and invasion of PC-3 prostate cancer cells (10-fold). In this study, the effects of MART-10 and 1alpha,25(OH)2D3 on proliferation, vitamin D receptor transactivation, vitamin D-binding protein (DBP) binding, CYP24A1 (24-OHase) substrate hydroxylation kinetics, and induction of CYP24A1 gene expression were compared in an androgen-dependent prostate cancer cell model, LNCaP. The results demonstrated that MART-10 was 1,000-fold more active than 1alpha,25(OH)2D3 in inhibiting LNCaP cell proliferation. MART-10 was more active than 1alpha,25(OH)2D3 in up-regulating a vitamin D receptor-responsive Luciferase construct and inducing CYP24A1 gene expression in LNCaP prostate cancer cells. In addition, MART-10 has a lower affinity for DBP and less substrate degradation by CYP24A1 compared to 1alpha,25(OH)2D3, indicating that MART-10 has more bioavailability and a longer half-life. Thus, these data suggest that MART-10 may be a potential candidate as a therapeutic agent for prostate cancer, especially for patients who fail in conventional therapies.
前列腺癌的高发病率以及缺乏针对转移性疾病的有效长期治疗方法，凸显了对更有效的非钙血症维生素D类似物的需求，它们可作为潜在的替代或联合前列腺癌治疗药物。在这些类似物中，19-去甲-1α,25-二羟基维生素D2（19-nor-1α,25(OH)2D2），即帕立骨化醇或泽米普利，在一些体内和体外系统中具有较低的钙血症效应，且与1α,25-二羟基维生素D3（1α,25(OH)2D3）具有同等效力。最近有研究表明，与1α,25(OH)2D3相比，帕立骨化醇的一种修饰类似物，19-去甲-2α-(3-羟丙基)-1α,25-二羟基维生素D3（MART-10）在抑制永生化正常前列腺细胞系（PZ-HPV-7）增殖方面更有效（高1000倍），在抑制PC-3前列腺癌细胞侵袭方面也更有效（高10倍）。在本研究中，在雄激素依赖性前列腺癌细胞模型LNCaP中比较了MART-10和1α,25(OH)2D3对细胞增殖、维生素D受体反式激活、维生素D结合蛋白（DBP）结合、CYP24A1（24-羟化酶）底物羟化动力学以及CYP24A1基因表达诱导的影响。结果表明，在抑制LNCaP细胞增殖方面，MART-10的活性比1α,25(OH)2D3高1000倍。在LNCaP前列腺癌细胞中，MART-10在上调维生素D受体反应性荧光素酶构建体和诱导CYP24A1基因表达方面比1α,25(OH)2D3更具活性。此外，与1α,25(OH)2D3相比，MART-10对DBP的亲和力较低，且被CYP24A1降解的底物较少，这表明MART-10具有更高的生物利用度和更长的半衰期。因此，这些数据表明MART-10可能是前列腺癌治疗药物的潜在候选者，尤其适用于传统治疗失败的患者。
