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Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells.

ABSTRACT: The efficacy of anticancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is overexpressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anticancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found that the peptide-drug conjugate is dramatically more effective than paclitaxel alone at inhibiting tumor growth in a prostate cancer xenograft model, delivering significantly higher levels of drug to the tumor site. We believe these studies open the way to the development of a new class of therapeutic compounds that exploit the EphA2 receptor for drug delivery to cancer cells.

SUBMITTER: Wang S

PROVIDER: S-EPMC3299084 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells.

Wang Si S Placzek William J WJ Stebbins John L JL Mitra Sayantan S Noberini Roberta R Koolpe Mitchell M Zhang Ziming Z Dahl Russell R Pasquale Elena B EB Pellecchia Maurizio M

Journal of medicinal chemistry 20120227 5

The efficacy of anticancer drugs is often limited by their systemic toxicities and adverse side effects. We report that the EphA2 receptor is overexpressed preferentially in several human cancer cell lines compared to normal tissues and that an EphA2 targeting peptide (YSAYPDSVPMMS) can be effective in delivering anticancer agents to such tumors. Hence, we report on the synthesis and characterizations of a novel EphA2-targeting agent conjugated with the chemotherapeutic drug paclitaxel. We found ...[more]

PMID: 22329578

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Project description:BackgroundThe nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) signaling pathway is activated in cells exposed to various stimuli, including those originating on the cell surface or in the nucleus. Activated NF-?B signaling is thought to enhance cell survival in response to these stimuli, which include chemotherapy and radiation. In the present effort, we determined which anticancer drugs preferentially activate NF-?B in colon cancer cells.MethodsNF-?B reporter cells were established and treated with 5-fluorouracil (5-FU, DNA/RNA damaging), oxaliplatin (DNA damaging), camptothecin (CTP, topoisomerase inhibitor), phleomycin (radiomimetic), or erlotinib (EGFR inhibitor). The activation of NF-?B was assessed by immunofluorescence for p65 translocation, luciferase assays, and downstream targets of NF-?B activation (cIAP2, and Bcl-XL) were evaluated by immunoblotting, by ELISA (CXCL8 and IL-6 in culture supernatants), or by gene expression analysis.ResultsColon cancer cells responded variably to different classes of therapeutic agents, and these agents initiated variable responses among different cell types. CPT activated NF-?B in SW480 colon cancer cells in a dose-dependent manner, but not in HCT116 cells that were either wild-type or deficient for p53. In SW480 colon cancer cells, NF-?B activation by CPT was accompanied by secretion of the cytokine CXCL8, but not by up-regulation of the anti-apoptotic genes, cIAP2 or Bcl-XL. On the contrary, treatment of HCT116 cells with CPT resulted in up-regulation of CXCR2, a receptor for CXCL8, without an increase in cytokine levels. In SW480 cells, NF-?B reporter activity, but not cytokine secretion, was inhibited by SM-7368, an NF-?B inhibitor.ConclusionThe results show that, in response to cancer therapeutic agents, NF-?B activation varies with the cellular make up and that drug-induced NF-?B activation may be functionally uncoupled from anti-apoptotic outcomes found for other stimuli. Some cancer cells in a heterogeneous tumor tissue may, under therapeutic pressure, release soluble factors that have paracrine activity on neighboring cells that express the cognate receptors.

Dataset Information

Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells.

Publications

Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells.

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