Anti-cancer IAP antagonists promote bone metastasis: a cautionary tale.
Anti-cancer IAP antagonists promote bone metastasis: a cautionary tale.
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DOI：
10.1007/s00774-013-0479-0
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发表时间：
2013-09
影响因子：
3.3
通讯作者：
Novack, Deborah Veis
中科院分区：
文献类型：
--
作者：
Yang, Chang;Novack, Deborah Veis
骨微环境是复杂的，包含骨形成成骨细胞、骨吸收破骨细胞、骨维持骨细胞、造血谱系细胞以及血管、神经和基质细胞。通过破骨细胞再吸收从骨基质中释放嵌入的生长因子已被证明参与改变骨微环境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与细胞凋亡抑制剂（IAP）蛋白水平升高相关，IAP拮抗剂代表了一类重要的新兴抗癌剂。IAP通过抑制半胱天冬酶和上调促存活蛋白发挥抗凋亡作用，至少部分通过激活经典NF-κB信号传导。此外，IAP在替代NF-κB通路中充当负调节剂，使得IAP拮抗剂刺激该通路。经典的NF-κB通路在IAP拮抗剂诱导的细胞凋亡中的作用已被广泛研究，而这些药物在旁路通路中的作用却很少受到关注。到目前为止，已经在临床前和早期临床试验中测试了几种IAP拮抗剂，并且已经显示出在使肿瘤细胞对凋亡敏感而没有显著副作用方面的前景。然而，最近的临床前证据表明IAP拮抗剂引起骨转移的风险增加，沿着促进骨质疏松症的潜力。本文就IAP拮抗剂、NF-κB通路、破骨细胞与骨转移的关系进行综述。鉴于IAP拮抗剂对骨微环境的影响，随着这些药物的进一步开发，应更多地关注这一组织和其他宿主组织。
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.
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影响因子：
7.3
作者：
Cai Q;Sun H;Peng Y;Lu J;Nikolovska-Coleska Z;McEachern D;Liu L;Qiu S;Yang CY;Miller R;Yi H;Zhang T;Sun D;Kang S;Guo M;Leopold L;Yang D;Wang S
通讯作者：
Wang S
影响因子：
64.5
作者：
Ferron M;Wei J;Yoshizawa T;Del Fattore A;DePinho RA;Teti A;Ducy P;Karsenty G
通讯作者：
Karsenty G
影响因子：
11.2
作者：
Bank, Alexander;Wang, Peng;Zhang, Lin
通讯作者：
Zhang, Lin
影响因子：
16
作者：
Bertrand, Mathieu J. M.;Milutinovic, Snezana;Barker, Philip A.
通讯作者：
Barker, Philip A.
DOI：
10.1111/j.1749-6632.2011.06244.x
发表时间：
2011-01-01
期刊：
SKELETAL BIOLOGY AND MEDICINE I
影响因子：
--
作者：
Faccio, Roberta
通讯作者：
Faccio, Roberta