Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305-5103, USA.
Endocr Relat Cancer. 2010 Jan 29;17(1):R19-38. doi: 10.1677/ERC-09-0139. Print 2010 Mar.
Calcitriol, the hormonally active form of vitamin D, exerts multiple anti-proliferative and pro-differentiating actions including cell cycle arrest and induction of apoptosis in many malignant cells, and the hormone is currently being evaluated in clinical trials as an anti-cancer agent. Recent research reveals that calcitriol also exhibits multiple anti-inflammatory effects. First, calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: i) suppression of the expression of cyclooxygenase-2, the enzyme that synthesizes PGs; ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme that inactivates PGs; and iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Second, calcitriol increases the expression of mitogen-activated protein kinase phosphatase 5 in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Third, calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of nuclear factor-kappaB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease.
骨化三醇，维生素 D 的活性形式，通过多种机制发挥抗增殖和促分化作用，包括细胞周期停滞和诱导许多恶性细胞凋亡，目前该激素正在临床试验中作为抗癌药物进行评估。最近的研究表明，骨化三醇还具有多种抗炎作用。首先，骨化三醇通过三种机制抑制促炎前列腺素 (PGs) 的合成和生物学作用：i) 抑制合成 PG 的酶——环氧化酶-2 的表达；ii) 上调 PG 失活酶——15-羟基前列腺素脱氢酶的表达；iii) 下调 PG 信号所必需的 PG 受体的表达。骨化三醇与非甾体抗炎药联合使用可协同抑制前列腺癌 (PCa) 细胞的生长，并为 PCa 提供一种潜在的治疗策略。其次，骨化三醇增加前列腺细胞中丝裂原活化蛋白激酶磷酸酶 5 的表达，导致随后抑制 p38 应激激酶信号和减少促炎细胞因子的产生。第三，骨化三醇还通过抑制核因子-κB 信号通路在 PCa 中发挥抗炎作用，从而产生强大的抗炎和抗血管生成作用。骨化三醇的其他重要直接作用及其抗炎作用的后果包括抑制肿瘤血管生成、侵袭和转移。我们假设，这些抗炎作用，除了骨化三醇的其他已知抗癌作用外，在其作为治疗 PCa 的潜在药物方面发挥着重要作用。骨化三醇或其类似物可用作化学预防剂，应在患有早期或癌前疾病的 PCa 患者的临床试验中进行评估。
