Coadministration of Epithelial Junction Opener JO-1 Improves the Efficacy and Safety of Chemotherapeutic Drugs

Beyer, Ines; Cao, Hua; Persson, Jonas; Song, Ha Yong; Richter, Maximilian; Feng, Qinghua; Yumul, Roma; Rensburg, Ruan van; Li, Zongyi; Berenson, Ronald J.; Carter, Darrick; Roffler, Steve R.; Drescher, Charles W.; Lieber, André

doi:10.1158/1078-0432.ccr-11-3213

Cited by 57 publications

(101 citation statements)

References 23 publications

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“…Our previous work has established that binding of Ad3 to DSG2 results in opening of epithelial junctions (3,34,35,52). This process is further enhanced by the production of PtDd during Ad3 infection (30).…”

Section: Discussionmentioning

confidence: 96%

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Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Wang

Ducournau

Saydaminova

et al. 2015

J Virol

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We recently discovered that desmoglein 2 (DSG2) is a receptor for human adenovirus species B serotypes Ad3, Ad7, Ad11, and Ad14. Ad3 is considered to be a widely distributed human pathogen. Ad3 binding to DSG2 triggers the transient opening of epithelial junctions. Here, we further delineate the mechanism that leads to DSG2-mediated epithelial junction opening in cells exposed to Ad3 and recombinant Ad3 fiber proteins. We identified an Ad3 fiber knob-dependent pathway that involves the phosphorylation of mitogen-activated protein (MAP) kinases triggering the activation of the matrix-metalloproteinase ADAM17. ADAM17, in turn, cleaves the extracellular domain of DSG2 that links epithelial cells together. The shed DSG2 domain can be detected in cell culture supernatant and also in serum of mice with established human xenograft tumors. We then extended our studies to Ad14 and Ad14P1. Ad14 is an important research and clinical object because of the recent appearance of a new, more pathogenic strain (Ad14P1). In a human epithelial cancer xenograft model, Ad14P1 showed more efficient viral spread and oncolysis than Ad14. Here, we tested the hypothesis that a mutation in the Ad14P1 fiber knob could account for the differences between the two strains. While our X-ray crystallography studies suggested an altered three-dimensional (3D) structure of the Ad14P1 fiber knob in the F-G loop region, this did not significantly change the fiber knob affinity to DSG2 or the intracellular signaling and DSG2 shedding in epithelial cancer cells. IMPORTANCE A number of widely distributed adenoviruses use the epithelial junction protein DSG2 as a receptor for infection and lateral spread. Interaction with DSG2 allows the virus not only to enter cells but also to open epithelial junctions which form a physicalbarrier to virus spread. Our study elucidates the mechanism beyond virus-triggered junction opening with a focus on adenovirus serotype 3. Ad3 binds to DSG2 with its fiber knob domain and triggers intracellular signaling that culminates in the cleavage of the extracellular domain of DSG2, thereby disrupting DSG2 homodimers between epithelial cells. We confirmed this pathway with a second DSG2-interacting serotype, Ad14, and its recently emerged strain Ad14P1. These new insights in basic adenovirus biology can be employed to develop novel drugs to treat adenovirus infection as well as be used as tools for gene delivery into epithelial tissues or epithelial tumors. W e recently discovered that desmoglein 2 (DSG2) is a receptor for human adenovirus species B serotypes Ad3, Ad7, Ad11, and Ad14 (1-3). DSG2 is a calcium-binding transmembrane glycoprotein belonging to the cadherin protein family. In epithelial cells of the respiratory, gastrointestinal, and urinary tracts, DSG2 is a component of the cell-cell adhesion structure (4). It is well established that in addition to maintaining cell adhesion, DSG2 is also involved in intracellular signaling (5). Its cytoplasmic tail interacts with a series of proteins, including plakoglobi...

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Section: Discussionmentioning

confidence: 96%

“…JO1 can be purified by affinity chromatography. We are currently developing JO1 derivatives for clinical applications to increase the penetration of chemotherapy drugs in epithelial tumors (34)(35)(36).…”

mentioning

confidence: 99%

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Wang

Ducournau

Saydaminova

et al. 2015

J Virol

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“…Most solid tumors are of epithelial origin, and although malignant cells are dedifferentiated, they maintain intercellular junctions, a key feature of epithelial cells, both in the primary tumor as well as in metastatic lesions (5,43). These intercellular junctions represent a protection mechanism against attacks by the host immune system and pose physical barriers that prevent intratumoral penetration and dissemination of cancer therapeutics, including monoclonal antibodies and chemotherapy drugs (5,43). When injected intravenously into mice with xenograft or syngeneic DSG2 transgenic tumors, JO-1 markedly enhanced therapeutic effects with a variety of chemotherapy drugs as well as monoclonal antibodies (3,5).…”

Section: Discussionmentioning

confidence: 99%

“…These intercellular junctions represent a protection mechanism against attacks by the host immune system and pose physical barriers that prevent intratumoral penetration and dissemination of cancer therapeutics, including monoclonal antibodies and chemotherapy drugs (5,43). When injected intravenously into mice with xenograft or syngeneic DSG2 transgenic tumors, JO-1 markedly enhanced therapeutic effects with a variety of chemotherapy drugs as well as monoclonal antibodies (3,5). In this study, we have shown that new affinity-enhanced versions of JO-1 (e.g., JO-4) increased the efficacy of cancer therapeutics significantly more than JO-1 (irinotecan, nab-paclitaxel, pegylated lipo- somal doxorubicin, and cetuximab) in four tumor models (A549, Ovc316, MDA-MB231, and TC1-DSG2).…”

Section: Discussionmentioning

confidence: 99%

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Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

Wang

Yumul

Cao

et al. 2013

J Virol

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f Human adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14, as well as a recently emerged strain of Ad14 (Ad14p1), use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. Unlike Ad interaction with CAR and CD46, structural details for Ad binding to DSG2 are still elusive. Using an approach based on Escherichia coli expression libraries of random Ad3 and Ad14p1 fiber knob mutants, we identified amino acid residues that, when mutated individually, ablated or reduced Ad knob binding to DSG2. These residues formed three clusters inside one groove at the extreme distal end of the fiber knob. The Ad3 fiber knob mutant library was also used to identify variants with increased affinity to DSG2. We found a number of mutations within or near the EF loop of the Ad3 knob that resulted in affinities to DSG2 that were several orders of magnitude higher than those to the wild-type Ad3 knob. Crystal structure analysis of one of the mutants showed that the introduced mutations make the EF loop more flexible, which might facilitate the interaction with DSG2. We recently identified DSG2 as the main receptor for a group of species B adenoviruses, including adenovirus serotype 3 (Ad3), a serotype which is widely distributed in the human population (1). We found that the DSG2-interacting domain(s) within Ad3 is formed by several fiber knobs (2). This specific mode of Ad3 fiber knob-DSG2 interaction provides a high avidity and is functionally relevant for opening of epithelial junctions (1, 2). The latter involves clustering of DSG2 and activation of pathways that are reminiscent of an epithelial-to-mesenchymal transition, including the phosphorylation of mitogen-activated protein kinase (MAPK) and the downregulation of junction protein expression (1,3,4). The ability to open epithelial junctions appears to be important for Ad3 penetration into and spread within airway epithelial cells (1, 2, 4). In a recent study, we attempted to find the minimal moiety within the Ad3 capsid that confers efficient binding to DSG2 (2). We generated a small recombinant protein which contains the Ad3 fiber knob and a domain that allows for the self-dimerization of trimeric Ad3 fiber knobs (JO-1) (2). JO-1 can be readily produced in Escherichia coli and purified by affinity chromatography. In polarized epithelial cell cultures, JO-1 triggered the opening of intercellular junctions, while intravenous injection of JO-1 into mice with epithelial tumors allowed for better penetration of anti-cancer drugs (3, 5).The first goal of the present study was to further delineate structural features of the Ad3 fiber knob-DSG2 interaction. This included identifying the amino acid residues within the Ad3 fiber knob that are involved in binding to DSG2 and creating JO-1 mutants with reduced and ablated binding to DSG2. The second goal of this study, which has translational relevance, was to further improve JO-1 by enhancing its affinity to DSG2, thereby increasing its therapeutic effect. This was done by identifying mutants with increased b...

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Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2⁺ Breast Cancer

Ngamcherdtrakul

Morry

et al. 2015

Adv Funct Materials

158

195

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In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2−) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation.

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Coadministration of Epithelial Junction Opener JO-1 Improves the Efficacy and Safety of Chemotherapeutic Drugs

Cited by 57 publications

References 23 publications

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2⁺ Breast Cancer

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Coadministration of Epithelial Junction Opener JO-1 Improves the Efficacy and Safety of Chemotherapeutic Drugs

Cited by 57 publications

References 23 publications

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Intracellular Signaling and Desmoglein 2 Shedding Triggered by Human Adenoviruses Ad3, Ad14, and Ad14P1

Structural and Functional Studies on the Interaction of Adenovirus Fiber Knobs and Desmoglein 2

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2+ Breast Cancer

Contact Info

Product

Resources

About

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2⁺ Breast Cancer