Smac Mimetic LBW242 Sensitizes XIAP-Overexpressing Neuroblastoma Cells for TNF-α–Independent Apoptosis

Eschenburg, Georg; Eggert, Angelika; Schramm, Alexander; Lode, Holger N.; Hundsdoerfer, Patrick

doi:10.1158/0008-5472.can-11-4072

Cited by 42 publications

(47 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results also offer potential for the evaluation of similar therapeutic strategies in other embryonal malignancies. It is notable that the activity of LBW242 in combination with cytotoxic chemotherapy has recently been shown in neuroblastoma-another common embryonal tumor of childhood (29).…”

Section: Discussionmentioning

confidence: 99%

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

Keating

Tsoli

Hallahan

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Medulloblastoma is the most common malignant brain tumor of childhood. Novel therapeutic strategies are urgently needed to overcome cytotoxic resistance. We hypothesized that antiapoptotic signals contribute to resistance and that treatment with proapoptotic agents could increase the efficacy of conventional therapies. A PCR array was used to assess the status of the apoptotic signaling pathway in medulloblastoma cells after treatment with cytotoxic chemotherapy. Treatment with cisplatin led to the upregulation of antiapoptotic signals, including inhibitor of apoptosis proteins (IAP), in medulloblastoma cells. We subsequently investigated the synergistic effect of a small-molecule IAP inhibitor, LBW242, in combination with cisplatin and/or radiotherapy in three human medulloblastoma cell lines and 5 short term primary patient medulloblastoma cultures. The addition of LBW242 to chemotherapy resulted in significantly increased antitumor activity with a similar effect observed in combination with radiotherapy. Measurement of caspase-8 and -9 activity indicated that the synergy resulted from induction of both the intrinsic and extrinsic apoptotic pathways. Apoptosis was confirmed by Annexin V staining and activation of caspases 3/7. Xenograft models were used to evaluate the mechanism of action and efficacy in vivo. The combination therapy significantly reduced the tumor burden in a medulloblastoma xenograft model and TUNEL analysis in a medulloblastoma orthograft confirmed in vivo induction of apoptosis. These findings support the strategy of targeting IAPs in combination with cytotoxic therapy as a novel treatment strategy for patients with medulloblastoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

Keating

Tsoli

Hallahan

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Mechanistic studies revealed that the synergistic activity of SMAC mimetics with chemotherapeutics is due to canonical NF-kB activation, TNFα production, and activation of the extrinsic apoptosis pathway [120]. In other studies, the reported synergy between SMAC mimetics and chemotherapeutics is reported as independent of TNFα, but dependent on the antagonism of XIAP [136, 137]. Recent studies have shown that genotoxic agents such as etoposide can activate cell death pathways via proteasome-dependent depletion of IAP proteins to promote the assembly of a cytoplasmic cell death-activating platform, ripoptosome [52, 53].…”

Section: Development Of Combination Therapies With Smac Mimetics For mentioning

confidence: 99%

Small-molecule SMAC mimetics as new cancer therapeutics

Bai

Smith

Wang

2014

Pharmacology & Therapeutics

169

172

View full text Add to dashboard Cite

Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments.

show abstract

“…Resistance to glucocorticoid-induced apoptosis is one of the major risk factors for relapse and poor outcome in ALL (39). For childhood neuroblastoma, no clear clinical data is available about XIAP expression and clinical outcome, although XIAP-inhibitors significantly affect tumor growth and death resistance of neuroblastoma in vitro and in vivo (40, 41). …”

Section: Xiap Overexpression In Cancermentioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Protein â€“ A Critical Death Resistance Regulator and Therapeutic Target for Personalized Cancer Therapy

2014

View full text Add to dashboard Cite

Defects in apoptosis regulation are one main cause of cancer development and may result from overexpression of anti-apoptotic proteins such as inhibitor of apoptosis proteins (IAPs). IAPs are cell death regulators that, among other functions, bind caspases, and interfere with apoptotic signaling via death receptors or intrinsic cell death pathways. All IAPs share one to three common structures, the so called baculovirus-IAP-repeat (BIR)-domains that allow them to bind caspases and other proteins. X-linked inhibitor of apoptosis protein (XIAP) is the most potent and best-defined anti-apoptotic IAP family member that directly neutralizes caspase-9 via its BIR3 domain and the effector caspases-3 and -7 via its BIR2 domain. A natural inhibitor of XIAP is SMAC/Diablo, which is released from mitochondria in apoptotic cells and displaces bound caspases from the BIR2/BIR3 domains of XIAP thereby reactivating cell death execution. The central apoptosis-inhibitory function of XIAP and its overexpression in many different types of advanced cancers have led to significant efforts to identify therapeutics that neutralize its anti-apoptotic effect. Most of these drugs are chemical derivatives of the N-terminal part of SMAC/Diablo. These “SMAC-mimetics” either specifically induce apoptosis in cancer cells or act as drug-sensitizers. Several “SMAC-mimetics” are currently tested by the pharmaceutical industry in Phase I and Phase II trials. In this review, we will discuss recent advances in understanding the function of IAPs in normal and malignant cells and focus on approaches to specifically neutralize XIAP in cancer cells.

show abstract

Smac Mimetic LBW242 Sensitizes XIAP-Overexpressing Neuroblastoma Cells for TNF-α–Independent Apoptosis

Cited by 42 publications

References 49 publications

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

Small-molecule SMAC mimetics as new cancer therapeutics

X-Linked Inhibitor of Apoptosis Protein â€“ A Critical Death Resistance Regulator and Therapeutic Target for Personalized Cancer Therapy

Contact Info

Product

Resources

About