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Journal of Bone and Mineral Metabolism

, Volume 31, Issue 5, pp 496–506 | Cite as

Anti-cancer IAP antagonists promote bone metastasis: a cautionary tale

  • Chang YangEmail author
  • Deborah Veis Novack
Invited Review

Abstract

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.

Keywords

Bone metastasis IAP antagonist Osteoclast NF-κB NIK 

Notes

Conflict of interest

All authors have no conflicts of interest.

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Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2013

Authors and Affiliations

  1. 1.Division of Bone and Mineral Diseases, Department of MedicineWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisUSA
  3. 3.Division of Bone and Mineral Diseases, Departments of Medicine and PathologyWashington University School of MedicineSt. LouisUSA

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