RANKL enhances the effect of an antagonist of inhibitor of apoptosis proteins (cIAPs) in RANK-positive breast cancer cells

S. Casimiro, I. Alho, M. Bettencourt, R. Pires, A. Lipton, L. Costa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objective: Between 65% and 75% of patients with metastatic breast cancer will have decreased 5-year survival and increased morbidity due to cancer relapse in bone. At this stage of disease treatment is palliative, but tumor-targeted compounds could add to the benefits of anti-resorptive agents, improving clinical outcome. Inhibitor-of-apoptosis proteins (IAPs) are overexpressed in many tumors and second mitochondria-derived activator of caspases (Smac) mimetics have been designed to antagonize IAPs. In this work we explored the use of AT-406. a Smac mimetic, to target the tumor compartment of bone metastases. Methods: Effect of AT-406 on cancer cells apoptosis. expression of IAPs and osteogenic potential was addressed in vitro using the RANK-positive MDA-MB-231 breast cancer cell line. Effect of AT-406 on osteoclastogenesis was determined by inducing the differentiation of the RAW 264.7 mouse monocytic cell line. Osteoclastogenesis was measured by TRAP staining and TRACP 5b quantification. Results: AT-406 increased apoptosis in MDA-MB-231 breast cancer cells in vitro, and activation of RANK-pathway improved this effect. RANKL stimuli induced a strong increase in C-IAP2. AT-406 increased osteoclast differentiation and activity, by up-regulating the osteogenic transcription factor Nfatcl, but also increased the apoptosis of mature osteoclasts in the absence of RANKL. Conclusions: Our results indicate that despite the anti-tumoral effect of AT-406. its use in the context of bone metastatic disease needs to be carefully monitored for the induction of increased bone resorption. We also hypothesize that the combination of AT-406 with anti-RANKL directed therapies could have a beneficial effect, especially in RANK-positive tumors.

Original languageEnglish (US)
Pages (from-to)116-122
Number of pages7
JournalJournal of Bone Oncology
Volume2
Issue number3
DOIs
StatePublished - 2013

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Inhibitor of Apoptosis Proteins
Breast Neoplasms
Neoplasms
Osteoclasts
Apoptosis
Caspases
Osteogenesis
Mitochondria
Bone and Bones
Cell Line
Bone Diseases
Bone Resorption
N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide
Palliative Care
Transcription Factors
Staining and Labeling
Neoplasm Metastasis
Morbidity
Recurrence
Survival

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Casimiro, S. ; Alho, I. ; Bettencourt, M. ; Pires, R. ; Lipton, A. ; Costa, L. / RANKL enhances the effect of an antagonist of inhibitor of apoptosis proteins (cIAPs) in RANK-positive breast cancer cells. In: Journal of Bone Oncology. 2013 ; Vol. 2, No. 3. pp. 116-122.
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abstract = "Objective: Between 65{\%} and 75{\%} of patients with metastatic breast cancer will have decreased 5-year survival and increased morbidity due to cancer relapse in bone. At this stage of disease treatment is palliative, but tumor-targeted compounds could add to the benefits of anti-resorptive agents, improving clinical outcome. Inhibitor-of-apoptosis proteins (IAPs) are overexpressed in many tumors and second mitochondria-derived activator of caspases (Smac) mimetics have been designed to antagonize IAPs. In this work we explored the use of AT-406. a Smac mimetic, to target the tumor compartment of bone metastases. Methods: Effect of AT-406 on cancer cells apoptosis. expression of IAPs and osteogenic potential was addressed in vitro using the RANK-positive MDA-MB-231 breast cancer cell line. Effect of AT-406 on osteoclastogenesis was determined by inducing the differentiation of the RAW 264.7 mouse monocytic cell line. Osteoclastogenesis was measured by TRAP staining and TRACP 5b quantification. Results: AT-406 increased apoptosis in MDA-MB-231 breast cancer cells in vitro, and activation of RANK-pathway improved this effect. RANKL stimuli induced a strong increase in C-IAP2. AT-406 increased osteoclast differentiation and activity, by up-regulating the osteogenic transcription factor Nfatcl, but also increased the apoptosis of mature osteoclasts in the absence of RANKL. Conclusions: Our results indicate that despite the anti-tumoral effect of AT-406. its use in the context of bone metastatic disease needs to be carefully monitored for the induction of increased bone resorption. We also hypothesize that the combination of AT-406 with anti-RANKL directed therapies could have a beneficial effect, especially in RANK-positive tumors.",
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RANKL enhances the effect of an antagonist of inhibitor of apoptosis proteins (cIAPs) in RANK-positive breast cancer cells. / Casimiro, S.; Alho, I.; Bettencourt, M.; Pires, R.; Lipton, A.; Costa, L.

In: Journal of Bone Oncology, Vol. 2, No. 3, 2013, p. 116-122.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RANKL enhances the effect of an antagonist of inhibitor of apoptosis proteins (cIAPs) in RANK-positive breast cancer cells

AU - Casimiro, S.

AU - Alho, I.

AU - Bettencourt, M.

AU - Pires, R.

AU - Lipton, A.

AU - Costa, L.

PY - 2013

Y1 - 2013

N2 - Objective: Between 65% and 75% of patients with metastatic breast cancer will have decreased 5-year survival and increased morbidity due to cancer relapse in bone. At this stage of disease treatment is palliative, but tumor-targeted compounds could add to the benefits of anti-resorptive agents, improving clinical outcome. Inhibitor-of-apoptosis proteins (IAPs) are overexpressed in many tumors and second mitochondria-derived activator of caspases (Smac) mimetics have been designed to antagonize IAPs. In this work we explored the use of AT-406. a Smac mimetic, to target the tumor compartment of bone metastases. Methods: Effect of AT-406 on cancer cells apoptosis. expression of IAPs and osteogenic potential was addressed in vitro using the RANK-positive MDA-MB-231 breast cancer cell line. Effect of AT-406 on osteoclastogenesis was determined by inducing the differentiation of the RAW 264.7 mouse monocytic cell line. Osteoclastogenesis was measured by TRAP staining and TRACP 5b quantification. Results: AT-406 increased apoptosis in MDA-MB-231 breast cancer cells in vitro, and activation of RANK-pathway improved this effect. RANKL stimuli induced a strong increase in C-IAP2. AT-406 increased osteoclast differentiation and activity, by up-regulating the osteogenic transcription factor Nfatcl, but also increased the apoptosis of mature osteoclasts in the absence of RANKL. Conclusions: Our results indicate that despite the anti-tumoral effect of AT-406. its use in the context of bone metastatic disease needs to be carefully monitored for the induction of increased bone resorption. We also hypothesize that the combination of AT-406 with anti-RANKL directed therapies could have a beneficial effect, especially in RANK-positive tumors.

AB - Objective: Between 65% and 75% of patients with metastatic breast cancer will have decreased 5-year survival and increased morbidity due to cancer relapse in bone. At this stage of disease treatment is palliative, but tumor-targeted compounds could add to the benefits of anti-resorptive agents, improving clinical outcome. Inhibitor-of-apoptosis proteins (IAPs) are overexpressed in many tumors and second mitochondria-derived activator of caspases (Smac) mimetics have been designed to antagonize IAPs. In this work we explored the use of AT-406. a Smac mimetic, to target the tumor compartment of bone metastases. Methods: Effect of AT-406 on cancer cells apoptosis. expression of IAPs and osteogenic potential was addressed in vitro using the RANK-positive MDA-MB-231 breast cancer cell line. Effect of AT-406 on osteoclastogenesis was determined by inducing the differentiation of the RAW 264.7 mouse monocytic cell line. Osteoclastogenesis was measured by TRAP staining and TRACP 5b quantification. Results: AT-406 increased apoptosis in MDA-MB-231 breast cancer cells in vitro, and activation of RANK-pathway improved this effect. RANKL stimuli induced a strong increase in C-IAP2. AT-406 increased osteoclast differentiation and activity, by up-regulating the osteogenic transcription factor Nfatcl, but also increased the apoptosis of mature osteoclasts in the absence of RANKL. Conclusions: Our results indicate that despite the anti-tumoral effect of AT-406. its use in the context of bone metastatic disease needs to be carefully monitored for the induction of increased bone resorption. We also hypothesize that the combination of AT-406 with anti-RANKL directed therapies could have a beneficial effect, especially in RANK-positive tumors.

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