Banwell Claire M, Singh Rena, Stewart Paul M, Uskokovic Milan R, Campbell Moray J
Department of Medicine, Division of Medical Sciences, University of Birmingham Medical School, Queen Elizabeth Hospital, Birmingham B15 2TT, UK.
Recent Results Cancer Res. 2003;164:83-98. doi: 10.1007/978-3-642-55580-0_5.
Breast and prostate cancer are leading causes of cancer death in the Western world. Hormone ablation is the primary therapy for invasive disease, but the tumour often recurs in an androgen or oestrogen receptor negative form for which novel therapies are sought urgently. The vitamin D receptor (VDR) may provide an important alternative therapeutic target. However, cancer cell line models from these tissues display a range of sensitivities to the antiproliferative effects of 1alpha,25dihydroxyvitamin D3 (1alpha,25(OH)2D3). The reason for apparent 1alpha,25(OH)2D3 insensitivity is currently unknown and we have investigated epigenetic mechanisms that may suppress the transcriptional activity of the VDR. Nuclear co-repressors have associated histone deacetylase (HDAC) activity, which keeps chromatin in a closed, transcriptionally silent state. We have found that the aggressive cancer cell lines with relative insensitivity to 1alpha,25(OH)2D3 have elevated nuclear co-repressor levels. For example, PC-3 prostate cancer cells have a significant 1.8-fold elevation in the co-repressor SMRT compared to normal epithelial cells (P < 0.05). We believe that a combination of elevated co-repressor level with reduced VDR content can cause 1alpha,25(OH)2D3 resistance. Consistent with this, we have shown that combining a low dose of HDAC inhibitor Trichostatin A (15 nM TSA) with 1alpha,25(OH)2D3 (100 nM) synergistically inhibits the proliferation of PC-3 prostate and MDA-MB-231 breast cancer cell lines. The inhibition of proliferation was potentiated further by treating cells with 19-nor-hexafluoride vitamin D3 analogues instead of 1alpha,25(OH)2D3, plus TSA. For example, the combination of 1alpha,25(OH)2D3 and TSA-inhibited MDA-MB-231 cell proliferation by 38% (+/-5%), whereas Ro26-2198 (1alpha,25-(OH)2-16,23Z-diene-26,27-F6-19-nor-D3) and TSA inhibited growth by 62% (+/-2%). Therapeutically the hypercalcaemic side effects associated with 1alpha,25(OH)2D3 could be minimized by combining low doses of potent 1a,25(OH)2D3 analogues with HDAC inhibitors as a novel anticancer regime for hormone-insensitive prostate and breast cancer.
乳腺癌和前列腺癌是西方世界癌症死亡的主要原因。激素消融是侵袭性疾病的主要治疗方法，但肿瘤常以雄激素或雌激素受体阴性的形式复发，对此急需新的治疗方法。维生素D受体（VDR）可能提供一个重要的替代治疗靶点。然而，来自这些组织的癌细胞系模型对1α,25-二羟基维生素D3（1α,25(OH)2D3）的抗增殖作用表现出一系列敏感性。目前尚不清楚1α,25(OH)2D3明显不敏感的原因，我们研究了可能抑制VDR转录活性的表观遗传机制。核共抑制因子具有相关的组蛋白脱乙酰酶（HDAC）活性，可使染色质保持在封闭的、转录沉默状态。我们发现，对1α,25(OH)2D3相对不敏感的侵袭性癌细胞系中核共抑制因子水平升高。例如，与正常上皮细胞相比，PC-3前列腺癌细胞中的共抑制因子SMRT显著升高1.8倍（P < 0.05）。我们认为，共抑制因子水平升高与VDR含量降低相结合可导致对1α,25(OH)2D3产生抗性。与此一致的是，我们已经表明，将低剂量的HDAC抑制剂曲古抑菌素A（15 nM TSA）与1α,25(OH)2D3（100 nM）联合使用可协同抑制PC-3前列腺癌细胞系和MDA-MB-231乳腺癌细胞系的增殖。用19-去甲-六氟维生素D3类似物代替1α,25(OH)2D3并加上TSA处理细胞，可进一步增强对增殖的抑制作用。例如，1α,25(OH)2D3和TSA的组合可抑制MDA-MB-231细胞增殖38%（±5%），而Ro26-2198（1α,25-(OH)2-16,23Z-二烯-26,27-F6-19-去甲-D3）和TSA可抑制生长62%（±2%）。在治疗上，将低剂量的强效1α,25(OH)2D3类似物与HDAC抑制剂联合使用作为激素不敏感型前列腺癌和乳腺癌的新型抗癌方案，可将与1α,25(OH)2D3相关联的高钙血症副作用降至最低。
