Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, 660 S. Euclid Ave, Box 8301, St. Louis, MO, 63110, USA,
J Bone Miner Metab. 2013 Sep;31(5):496-506. doi: 10.1007/s00774-013-0479-0. Epub 2013 Jun 6.
The bone microenvironment is complex, containing bone-forming osteoblasts, bone-resorbing osteoclasts, bone-maintaining osteocytes, hematopoietic lineage cells, as well as blood vessels, nerves, and stromal cells. Release of embedded growth factors from the bone matrix via osteoclast resorption has been shown to participate in the alteration of bone microenvironment to facilitate tumor metastasis to this organ. Many types of malignancies including solid tumors and leukemias are associated with elevated levels of inhibitor of apoptosis (IAP) proteins, and IAP antagonists represent an important emerging class of anti-cancer agents. IAPs exert anti-apoptotic roles by inhibiting caspases and upregulating pro-survival proteins, at least in part by activating classical NF-κB signaling. In addition, IAPs act as negative regulators in the alternative NF-κB pathway, so that IAP antagonists stimulate this pathway. The role of the classical NF-κB pathway in IAP antagonist-induced apoptosis has been extensively studied, whereas much less attention has been paid to the role of these agents in the alternative pathway. Thus far, several IAP antagonists have been tested in preclinical and early stage clinical trials, and have shown promise in sensitizing tumor cells to apoptosis without significant side effects. However, recent preclinical evidence suggests an increased risk of bone metastasis caused by IAP antagonists, along with potential for promoting osteoporosis. In this review, the connection between IAP antagonists, the alternative NF-κB pathway, osteoclasts, and bone metastasis are discussed. In light of these effects of IAP antagonists on the bone microenvironment, more attention should be paid to this and other host tissues as these drugs are developed further.
骨微环境复杂，包含成骨细胞、破骨细胞、骨细胞、造血谱系细胞以及血管、神经和基质细胞。破骨细胞通过吸收骨基质来释放嵌入的生长因子，这被证明参与了骨微环境的改变，以促进肿瘤转移到该器官。包括实体瘤和白血病在内的许多类型的恶性肿瘤都与凋亡抑制因子（IAP）蛋白水平升高有关，IAP 拮抗剂代表了一类重要的新兴抗癌药物。IAP 通过抑制半胱天冬酶和上调促生存蛋白来发挥抗凋亡作用，至少部分是通过激活经典 NF-κB 信号通路。此外，IAP 作为替代 NF-κB 通路的负调节剂，因此 IAP 拮抗剂刺激该通路。经典 NF-κB 通路在 IAP 拮抗剂诱导凋亡中的作用已得到广泛研究，而这些药物在替代途径中的作用则受到较少关注。迄今为止，已有几种 IAP 拮抗剂在临床前和早期临床试验中进行了测试，并且在不引起明显副作用的情况下增强肿瘤细胞对凋亡的敏感性方面显示出前景。然而，最近的临床前证据表明 IAP 拮抗剂会增加骨转移的风险，并可能促进骨质疏松症。在这篇综述中，讨论了 IAP 拮抗剂、替代 NF-κB 通路、破骨细胞和骨转移之间的联系。鉴于 IAP 拮抗剂对骨微环境的这些影响，在进一步开发这些药物时，应更加关注这些影响和其他宿主组织。
