TY - JOUR
T1 - Anti-cancer IAP antagonists promote bone metastasis
T2 - A cautionary tale
AU - Yang, Chang
AU - Novack, Deborah Veis
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
KW - Bone metastasis
KW - IAP antagonist
KW - NF-κB
KW - NIK
KW - Osteoclast
UR - http://www.scopus.com/inward/record.url?scp=84885431355&partnerID=8YFLogxK
U2 - 10.1007/s00774-013-0479-0
DO - 10.1007/s00774-013-0479-0
M3 - Review article
C2 - 23740289
AN - SCOPUS:84885431355
SN - 0914-8779
VL - 31
SP - 496
EP - 506
JO - Journal of Bone and Mineral Metabolism
JF - Journal of Bone and Mineral Metabolism
IS - 5
ER -