IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

Shekhar, Tanmay M.; Miles, Mark A.; Gupte, Ankita; Taylor, Scott; Tascone, Brianna; Walkley, Carl R.; Hawkins, Christine J.

doi:10.18632/oncotarget.8980

Cited by 17 publications

(27 citation statements)

References 109 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of XIAP increases TNFα-induced cell death in melanoma [29] and OS [30]. This observation is also reported in the current study, indicating a role for XIAP in protection against TNFα-induced cell death in the OS cell lines investigated in this study.…”

Section: Discussionsupporting

confidence: 91%

Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death

et al. 2020

View full text Add to dashboard Cite

Fas-associated protein with death domain (FADD) was first identified for its role in linking death receptors to the apoptotic signaling pathway with subsequent cell death. Later studies reported non-apoptotic functions for FADD in normal cells and cancer cells. Non-apoptotic functions for FADD in osteosarcoma (OS) have not been reported. In this study, FADD protein expression was knocked down in human CCHOSD, LM7, and SaOS2 OS cell lines followed by assessment of sensitivity to TNFα-or TRAIL-induced cell death. Knock down of FADD significantly increased TNFα-induced cell death in LM7 and SaOS2 cell lines. The mode of TNFα-induced cell death was apoptosis and not necroptosis. Inhibition of nuclear factor kappa B (NFκB) in wildtype cells increased TNFα-induced cell death to similar levels observed in FADD knockdown cells, suggesting a role for FADD in NFκB pro-survival cell signaling. In addition, knock down of FADD increased SMAC mimetic-mediated TNFα-induced cell death in all cell lines studied. The results of this study indicate that FADD has a pro-survival function in OS following TNFα treatment that involves NFκB signaling. The results also indicate that the pro-survival function of FADD is associated with XIAP activity.

show abstract

Section: Discussionsupporting

confidence: 91%

Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death

et al. 2020

View full text Add to dashboard Cite

show abstract

“…We only observed some cell killing at doses exceeding those achieved clinically 16 , even in KMS28PE cells that harbor biallelic deletion of cIAP1/2, indicating that killing was likely due to off target effects of LCL161 33,34 . Consistent with the strong pro-survival role for TNF in MM mediated by NFkB activation 35 , but in contrast to the pro-apoptotic effects of TNF in combination with IAPa reported in other pre-clinical models 2–4,9,13 , the addition of exogenous TNF did not potentiate LCL161 activity nor induce cell death in HMCLs in vitro , but rescued the lethality observed at non clinically relevant concentrations of LCL161 (Supplementary Fig. 1 b ).…”

Section: Resultssupporting

confidence: 85%

IAP antagonists induce anti-tumor immunity in multiple myeloma

Chesi

Mirza

Garbitt

et al. 2016

Nat Med

149

170

View full text Add to dashboard Cite

The cellular inhibitor of apoptosis cIAP1 and −2 are amplified in about 3% of cancers, and were identified in multiple malignancies as potential therapeutic targets due to their role in evasion of apoptosis. Consequently, small molecule IAP antagonists, like LCL161, have entered clinical trials for their ability to induce TNF-mediated apoptosis of cancer cells. However, cIAP1 and −2 are recurrently homozygously deleted in multiple myeloma resulting in constitutive activation of the non-canonical NFkB pathway. It was therefore counterintuitive to observe a robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and patients with relapsed-refractory myeloma, where addition of cyclophosphamide resulted in a median progression free survival of 10 months. This effect is not due to direct induction of tumor cell death, but rather to upregulation of a tumor cell autonomous type I interferon signaling and a strong inflammatory response with activation of macrophages and dendritic cells resulting in phagocytosis of tumor cells. Treatment with LCL161 established long-term anti-tumor protection and cure in a fraction of transgenic Vk*MYC mice. Remarkably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all treated mice.

show abstract

“…Further work would be needed to define the basis for this heterogeneity, but it may reflect differences between tumours in expression of navitoclax‐resistant members of the pro‐survival branch of the Bcl‐2 family . “IAP antagonists” (also known as “Smac mimetics”) are another class of new anti‐cancer agents, which were recently documented to render osteosarcoma cells sensitive to the lethal effects of TNFα in vitro . Although those data suggest that inhibitor of apoptosis protein (IAP) antagonists may be useful for treating human osteosarcoma patients, these drugs stimulate severe cytokine release syndrome in dogs so would unfortunately not be suitable for treating canine patients.…”

Section: Discussionmentioning

confidence: 99%

“…55 "IAP antagonists" (also known as "Smac mimetics") are another class of new anti-cancer agents, 56 which were recently documented to render osteosarcoma cells sensitive to the lethal effects of TNFα in vitro. 57 Although those data suggest that inhibitor of apoptosis protein (IAP) antagonists may be useful for treating human osteosarcoma patients, these drugs stimulate severe cytokine release syndrome in dogs 58,59 so would unfortunately not be suitable for treating canine patients. We therefore chose not to evaluate IAP antagonists in this study.…”

Section: Discussionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

View full text Add to dashboard Cite

Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.

show abstract

IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

Cited by 17 publications

References 109 publications

Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death

Knock down of Fas-Associated Protein with Death Domain (FADD) Sensitizes Osteosarcoma to TNFα-induced Cell Death

IAP antagonists induce anti-tumor immunity in multiple myeloma

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Contact Info

Product

Resources

About