Dataset Information

Smac-mimetics reduce numbers and viability of human osteoclasts.

ABSTRACT: Elevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-?B and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of drugs that block RIPK1 ubiquitination and shifts RIPK1 to activation of apoptosis or necroptosis. In this manuscript, we show that the two SM birinapant and LCL-161 reduced the number and viability of primary human OC, and induced TNF-dependent cell death in OC precursors (pre-OC). Birinapant was more cytotoxic than LCL-161 and induced predominantly apoptosis and to some degree necroptosis. Both inhibitors restrained osteoclastogenesis induced by myeloma patient bone-marrow aspirates. SM has gained attention as novel treatment strategies both for cancer and chronic inflammatory pathologies, but limited information has been available on interactions with primary human immune cells. As LCL-161 is in phase 2 clinical studies for multiple myeloma, we propose that SM might possess additional benefits in reducing bone degradation in myeloma patients. Taken together, we show that SM reduces human osteoclastogenesis, and that these compounds may represent promising drug candidates for pathological bone degradation.

SUBMITTER: Moen IN

PROVIDER: S-EPMC7895921 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Smac-mimetics reduce numbers and viability of human osteoclasts.

Moen Ingrid Nyhus IN Westhrin Marita M Håland Erling E Haug Markus M Nonstad Unni U Klaharn Merisa M Standal Therese T Starheim Kristian K KK

Cell death discovery 20210219 1

Elevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-κB and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of ...[more]

PMID: 33608503

Similar Datasets

Project description:Smac/DIABLO is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Smac promotes apoptosis at least in part through antagonizing inhibitor of apoptosis proteins (IAPs), including XIAP, cIAP-1, and cIAP-2. Smac interacts with these IAPs via its N-terminal AVPI binding motif. There has been an enormous interest in academic laboratories and pharmaceutical companies in the design of small-molecule Smac mimetics as potential anticancer agents. This task is particularly challenging because it involves targeting protein-protein interactions. Nevertheless, intense research has now generated potent, specific, cell-permeable small-molecule peptidomimetics and nonpeptidic mimetics. To date, two types of Smac mimetics have been reported, namely, monovalent and bivalent Smac mimetics. The monovalent compounds are designed to mimic the binding of a single AVPI binding motif to IAP proteins, whereas the bivalent compounds contain two AVPI binding motif mimetics tethered together through a linker. Studies from several groups have clearly demonstrated that both monovalent and bivalent Smac mimetics not only enhance the antitumor activity of other anticancer agents but also can induce apoptosis as single agents in a subset of human cancer cell lines in vitro and are capable of achieving tumor regression in animal models of human cancer. In general, bivalent Smac mimetics are 100-1000 times more potent than their corresponding monovalent Smac mimetics in induction of apoptosis in tumor cells. However, properly designed monovalent Smac mimetics can achieve oral bioavailability and may have major advantages over bivalent Smac mimetics as potential drug candidates. In-depth insights on the molecular mechanism of action of Smac mimetics have been provided by several independent studies. It was shown that Smac mimetics induce apoptosis in tumor cells by targeting cIAP-1/-2 for the rapid degradation of these proteins, which leads to activation of nuclear factor kappaB (NF-kappaB) and production and secretion of tumor necrosis factor alpha (TNFalpha). TNFalpha promotes formation of a receptor-interacting serine-threonine kinase 1 (RIPK1)-dependent caspase-8-activating complex, leading to activation of caspase-8 and -3/-7 and ultimately to apoptosis. For the most efficient apoptosis induction, Smac mimetics also need to remove the inhibition of XIAP to caspase-3/-7. Hence, Smac mimetics induce apoptosis in tumor cells by targeting not only cIAP-1/-2 but also XIAP. The employment of potent, cell-permeable, small-molecule Smac mimetics has yielded important insights into the regulation of apoptosis by IAP proteins. To date, at least one Smac mimetic has been advanced into clinical development. Several other Smac mimetics are in an advanced preclinical development stage and are expected to enter human clinical testing for the treatment of cancer in the near future.

Dataset Information

Smac-mimetics reduce numbers and viability of human osteoclasts.

Publications

Smac-mimetics reduce numbers and viability of human osteoclasts.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets