Design of Small-Molecule Peptidic and Nonpeptidic Smac Mimetics

Sun, Haiying; Nikolovska‐Coleska, Zaneta; Yang, Chao; Qian, Dongguang; Lu, Jianfeng; Qiu, Su; Bai, Longchuan; Peng, Yunfeng; Cai, Qian; Wang, Shaomeng

doi:10.1021/ar8000553

Cited by 153 publications

(155 citation statements)

References 48 publications

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“…These results are in line with previously reported data on XIAP expression in NSCLC tumours (75,84,85). Although the expression of XIAP and cIAPs in NSCLC tumours did not predict the response to classic chemotherapy in patients with advanced NSCLC (84), treatment of NSCLC cells as well as other cancer cells with novel synthetic Smac-mimetic antagonists of XIAP and cIAPs induces apoptosis in these cells (35,36,86,87) or sensitises them against apoptosis inducers such as nonsteroidal anti-inflammatory drugs and TRAIL (88,89).…”

Section: ------------------------------------------------------------supporting

confidence: 91%

Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Kr̆epela

Dankova²,

Moravcikova³

et al. 2009

Int J Oncol

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Abstract.Members of the inhibitor of apoptosis protein (IAP) family, survivin and X-chromosome-linked IAP (XIAP), contribute to apoptosis resistance of cancer cells, and an increase in their expression may elevate the apoptotic threshold of malignant tumours during their growth and progression. In the present study, we investigated the expression status of survivin and its interactants hepatitis B X-interacting protein (HBXIP) and XIAP in non-small cell lung carcinoma (NSCLC) cell lines and NSCLC tumours and matched lungs from surgically treated patients in relation to their clinicopathological data. The expression of survivin, HBXIP and XIAP mRNAs was quantitated by real-time RT-PCR. The expression of survivin and XIAP proteins was analysed by Western blotting and ELISA. Survivin mRNA and protein levels were highly upregulated in NSCLC cells and tissues as compared to the lungs. In fact, the levels of survivin mRNA and protein in the tumours were more than 10-fold higher in 96 (64%) and 72 (82%) of the 150 and 88 examined NSCLC patients, respectively. The expression of survivin mRNA was higher in squamous cell lung carcinomas than in lung adenocarcinomas (LACs; P=0.003) and in less-differentiated tumours than in well-differentiated ones (P=0.007). The level of survivin protein was higher in stage IB and stage II+III tumours (P=0.049 and P=0.044), than in stage IA tumours. The BIRC5 promoter polymorphism at nucleotide -31 did not influence the expression of survivin mRNA and protein in NSCLC cells and tumours. HBXIP mRNA was abundantly expressed in NSCLC cell lines and NSCLC tumours and lungs, while its level was comparable in the tumours and lungs. The expression of XIAP mRNA in NSCLC cell lines and NSCLC tumours and lungs was not significantly different. However, the expression of XIAP protein was higher in NSCLC tumours, particularly in LACs, as compared to the lungs (P=0.017 and P=0.004). In conclusion, the overexpression of survivin in the majority of NSCLCs together with the abundant or upregulated expression of HBXIP and XIAP suggest that tumours are endowed with resistance against a variety of apoptosis-inducing conditions.

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confidence: 91%

Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Kr̆epela

Dankova²,

Moravcikova³

et al. 2009

Int J Oncol

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“…72 --74 In an attempt to improve the potency and the pharmacological characteristics of IAP antagonists, a number of different peptidomimetics mimicking the N-terminal domain of Smac were subsequently designed. 75 --80 Although these compounds were initially composed as monovalent agents, 80,81 further drugdiscovery efforts resulted in the generation of bivalent IAP antagonists made of two monovalent motifs with a central chemical linker. 82 --84 In general, bivalent IAP antagonists were described to exhibit higher binding affinities for IAP proteins and higher potency than monovalent IAP antagonists to induce cell death and to inhibit tumor growth.…”

Section: Survivin In Hematological Malignanciesmentioning

confidence: 99%

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Fulda

2012

Leukemia

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Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest.

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“…Thirdly, it could be envisioned to employ the Livin-inhibiting peptides as a basis for design of peptidomimetics. This approach has been successfully followed by the development of Smac mimetics blocking IAPs [17,19]. Fourthly, it is likely that the Livin-binding peptides, which induce therapeutically desired cellular phenotypes such as pro-apoptic sensitization, bind to functionally important domains on Livin.…”

Section: Discussionmentioning

confidence: 99%

“…These peptides shared no obvious sequence homologies with the natural Livin inhibitor Smac, and consequently no similarity with any of the previously generated Smac-like peptides or peptidomimetics blocking IAPs [19]. We characterized the binding of the peptides to both known Livin isoforms (Livin a and Livin b), investigated their potential to sensitize livin-expressing tumor cells toward apoptosis, analyzed their effects on the levels and intracellular distribution of Livin, and assessed their influence on the growth of livin-expressing cells.…”

Section: Introductionmentioning

confidence: 92%

Isolation of peptides blocking the function of anti-apoptotic Livin protein

Crnković-Mertens

Bulkescher

Mensger

et al. 2010

Cell. Mol. Life Sci.

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Livin (ML-IAP) is a cancer-associated member of the inhibitor of apoptosis protein (IAP) family. By yeast two-hybrid screening of a randomized peptide expression library, we isolated short linear peptides that specifically bind to Livin, but not to other IAPs. Intracellular expression of the peptides sensitized livin-expressing cancer cells toward different pro-apoptotic stimuli. The bioactive peptides neither showed sequence homologies to Smac-derived IAP inhibitors, nor did they interfere with the binding of Livin to Smac. Intracellular expression of the peptides did not affect the levels or the subcellular distribution of Livin. Growth of livin-expressing tumor cells was inhibited in colony formation assays by the Livin-targeting peptides. These findings provide evidence that the targeted inhibition of Livin by peptides represents a viable approach for the apoptotic sensitization and growth inhibition of tumor cells. The inhibitory peptides isolated here could form a novel basis for the development of therapeutically useful Livin inhibitors.

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Design of Small-Molecule Peptidic and Nonpeptidic Smac Mimetics

Cited by 153 publications

References 48 publications

Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Increased expression of inhibitor of apoptosis proteins, survivin and XIAP, in non-small cell lung carcinoma

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Isolation of peptides blocking the function of anti-apoptotic Livin protein

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