ArticleJournal of experimental & clinical cancer research : CR2016
LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC.
Article in Journal of experimental & clinical cancer research : CR, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 67 citations in OpenAlex.
- Review
- Hematopoietic expression of cIAP2 drives inflammation and heart failure after myocardial infarction.Nature cardiovascular research · 2026Article
- IAPs in cancers: molecular mechanisms, clinical prognostic value, and translational therapeutic potential.Journal of translational medicine · 2026Review
- Integration of single-cell and bulk transcriptomics reveals the association of manganese metabolism-related genes with prognosis and immune infiltration in lung adenocarcinoma.Clinical & translational immunology · 2026Article
- Article
- Targeting the inhibitors of apoptosis proteins (IAPs) to combat drug resistance in cancers.Frontiers in pharmacology · 2025Review
- Research Progress in the Small Molecule Smac Mimetics in Combination Therapy of Cancer.Current medicinal chemistry · 2025Review
- Enhancing immunotherapy efficacy against MHC-I deficient triple-negative breast cancer using LCL161-loaded macrophage membrane-decorated nanoparticles.Acta pharmaceutica Sinica. B · 2024Article
- The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer.Scientific reports · 2024Article
- SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects.Mini reviews in medicinal chemistry · 2024Review
- Dysregulation of PLOD2 Promotes Tumor Metastasis and Invasion in Hepatocellular Carcinoma.Journal of clinical and translational hepatology · 2023Article
- A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies.The oncologist · 2023Article
- Increased migration and motility in XIAP-null cells mediated by the C-RAF protein kinase.Scientific reports · 2022Article
- Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma.Frontiers in oncology · 2022Article
- Inhibition of BIRC2 Sensitizes α7-HPV-Related Cervical Squamous Cell Carcinoma to Chemotherapy.International journal of molecular sciences · 2021Article
- IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB- and caspase-8-dependent mechanisms.Blood advances · 2021Article
- Review
- SMAC exhibits anti-tumor effects in ECA109 cells by regulating expression of inhibitor of apoptosis protein family.World journal of clinical cases · 2021Article
- Light-Controllable PROTACs for Temporospatial Control of Protein Degradation.Frontiers in cell and developmental biology · 2021Review
- Comprehensive Analysis of Inhibitor of Apoptosis Protein Expression and Prognostic Significance in Non-Small Cell Lung Cancer.Frontiers in genetics · 2021Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundLCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.
methodsCellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.
resultsThe expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.
conclusionThus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.
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