ArticleJournal of experimental & clinical cancer research : CR2017
The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer.
Article in Journal of experimental & clinical cancer research : CR, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- SMARCA4 deficiency contributes to platinum resistance in non-small cell lung cancer by activating the NF-κB-BIRC2/BIRC3 signaling axis.Journal of thoracic disease · 2026Article
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- Trametinib Thwarts Activation of Survival Pathways Induced by Pro-ferroptotic Drug Conjugate ACXT-3102 Resulting in Enhanced Pancreatic Cancer Cell Death.Molecular cancer therapeutics · 2025Article
- Ternary Complex Components Responsible for Rapid LDL Internalization as Biomarkers for Breast Cancer Associated with Proliferation and Early Recurrence.Cancer research communications · 2025Article
- Cytotoxic sigma-2 ligands trigger cancer cell death via cholesterol-induced-ER-stress.Cell death & disease · 2024Article
- The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer.Scientific reports · 2024Article
- The targeted SMAC mimetic SW IV-134 augments platinum-based chemotherapy in pre-clinical models of ovarian cancer.BMC cancer · 2022Article
- BH3-mimetics: recent developments in cancer therapy.Journal of experimental & clinical cancer research : CR · 2021Review
- NF-κB and Pancreatic Cancer; Chapter and Verse.Cancers · 2021Review
- Review
- Development of small molecule fluorescent dye drug conjugates in targeted cancer therapy.American journal of clinical and experimental urology · 2021Article
- TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death.Cell death discovery · 2019Article
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9 authors.
Funding
Abstract
backgroundPancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine.
methodsUsing the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer.
resultsThe sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer.
conclusionWe believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation.
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