Therapeutic Targeting of TLR9 Inhibits Cell Growth and Induces Apoptosis in Neuroblastoma

Brignole, Chiara; Marimpietri, Danilo; Paolo, Daniela Di; Perri, Patrizia; Morandi, Fabio; Pastorino, Fabio; Zorzoli, Alessia; Pagnan, Gabriella; Loi, Monica; Caffa, Irene; Erminio, Giovanni; Haupt, Riccardo; Gambini, Claudio; Pistoia, Vito; Ponzoni, Mirco

doi:10.1158/0008-5472.can-10-1251

Cited by 66 publications

(50 citation statements)

References 43 publications

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“…Numerous targeted nanoparticles against different antigens have been described in the literature for potential treatment of solid tumors (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The majority of those studies focused on the selection and design of nanoparticles and/or targeting moieties.…”

Section: Introductionmentioning

confidence: 99%

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

Hendriks

Klinz

Reynolds

et al. 2013

Molecular Cancer Therapeutics

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Numerous targeted nanotherapeutics have been described for potential treatment of solid tumors. Although attention has focused on antigen selection and molecular design of these systems, there has been comparatively little study of how cellular heterogeneity influences interaction of targeted nanoparticles with tumor cells. Antigens, such as HER2/ERBB2, are heterogeneously expressed across different indications, across patients, and within individual tumors. Furthermore, antigen expression in nontarget tissues necessitates optimization of the therapeutic window. Understanding the performance of a given nanoparticle under different regimens of antigen expression has the ability to inform patient selection and clinical development decisions. In this work, HER2-targeted liposomal doxorubicin was used as a modeltargeted nanoparticle to quantitatively investigate the effect of HER2 expression levels on delivery of doxorubicin to the nucleus. We find quantitatively greater nuclear doxorubicin delivery with increasing HER2 expression, exhibiting a threshold effect at approximately 2 Â 10 5 HER2 receptors/cell. Kinetic modeling indicated that the threshold effect arises from multiple low-affinity interactions between the targeted liposome and HER2. These results support previous data showing little or no uptake into human cardiomyocytes, which express levels of HER2 below the threshold. Finally, these results suggest that HER2-targeted liposomal doxorubicin may effectively target tumors that fall below traditional definitions of HER2-positive tumors, thereby expanding the potential population of patients that might benefit from this agent. Mol Cancer Ther; 12(9); 1816-28. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 99%

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

Hendriks

Klinz

Reynolds

et al. 2013

Molecular Cancer Therapeutics

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“…Following CpG-ODN binding, TLR9 associates with the adaptor molecule MyD88 resulting in activation of the IL-1 receptor-associated kinase family and mitogen-activated protein kinases. The latter events activate NF-κB and apoptosis [28,29]. …”

Section: Discussionmentioning

confidence: 99%

Small Interfering RNA Targeting Toll-Like Receptor 9 Protects Mice against Polymicrobial Septic Acute Kidney Injury

Liu

Li²,

et al. 2013

Nephron Exp Nephrol

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Background/Aims: Although recent reports suggest that Toll-like receptor (TLR) 9 is associated with the pathogenesis of polymicrobial septic acute kidney injury (AKI), it is still unclear whether and how renal TLR9 is involved in the development of polymicrobial septic AKI. This study aimed to determine whether the expression of TLR9 in mouse renal cells is related to the development of polymicrobial septic AKI. Methods: The efficacy of small interfering RNA (siRNA) targeting TLR9 was tested in a cultured murine macrophage cell line (RAW264.7 cells). The most potent siRNA was transfected into mice using the hydrodynamic method prior to the induction of polymicrobial septic AKI being induced by cecal ligation and puncture (CLP). TLR9 knockdown was determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting in RAW264.7 cells and kidney tissues. The levels of serum creatinine and blood urea nitrogen (BUN) and the renal histopathology assessment were determined at 6-, 12-, and 24-hour time points after CLP, and renal cell apoptosis was studied at 24 h. The 4- and 7-day survival rates of mice were also observed. Results: We found that mice developed AKI in our model of polymicrobial sepsis, despite fluid and antibiotic resuscitation, which resembles human sepsis. siRNA to TLR9 successfully silenced the induction of renal TLR9 gene and protein expression following CLP. Effective silencing of renal TLR9 expression decreased renal cell apoptosis, mitigated the severity of AKI, and increased the survival of mice. Conclusions: Our data demonstrates the induction of TLR9 expression in mouse kidney tissue following CLP. Renal cell apoptosis and AKI in our model of polymicrobial sepsis are dependent on TLR9. Thus, TLR9 may play a critical role in the pathophysiology of polymicrobial septic AKI.

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“…Clearly, in order for TLR agonists to work directly on tumors cells, it is imperative that the cancer cells express the cognate TLR. TLRs may also promote apoptosis, vascular permeability, lymphocyte homing to the tumor site and improve the sensitivity of the tumor to proapoptotic cytokines [24][25][26].…”

Section: Harnessing Tlr Ligands For Cancer Vaccinesmentioning

confidence: 99%

Cancer Vaccination, Will You Have To Pay The Toll?

Gregory¹

2013

J Vaccines Vaccin

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Cancer vaccines based on patient-derived, autologous immune cells are actively being pursued as a novel strategy to utilize the body's natural defenses against malignancy. Harnessing the ability of the immune system to fight cancer involves overcoming many obstacles including tumor-specific targeting, overcoming tolerance, and generating effective tumoricidal responses. Co-administration of immune activating adjuvants may hold the key to breaking through several of these barriers. Toll-like receptors (TLR) are pathogen sensors of the innate immune system that activate proinflammatory responses to fight infection and initiate adaptive immune responses. TLRs are increasingly being explored in combination with cancer vaccine strategies since they may have the potential to enhance immunotherapy by promoting tumor-specific immunity. This review will focus on recent basic and clinical research on the use of TLR agonists in cancer therapy.

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Therapeutic Targeting of TLR9 Inhibits Cell Growth and Induces Apoptosis in Neuroblastoma

Cited by 66 publications

References 43 publications

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

Impact of Tumor HER2/ERBB2 Expression Level on HER2-Targeted Liposomal Doxorubicin-Mediated Drug Delivery: Multiple Low-Affinity Interactions Lead to a Threshold Effect

Small Interfering RNA Targeting Toll-Like Receptor 9 Protects Mice against Polymicrobial Septic Acute Kidney Injury

Cancer Vaccination, Will You Have To Pay The Toll?

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