5′-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells

Li, Dengzhe; Gale, Robert Peter; Liu, Yanfeng; Bao-xia, Lei; Wang, Yuan; Diao, Dongmei; Zhang, Mei

doi:10.1016/j.leukres.2017.03.010

Cited by 23 publications

(17 citation statements)

References 23 publications

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“…Although RIG-I-dependent anticancer immunity has been reported in several cancers, including pancreatic cancer, hepatocellular carcinoma (40), leukemias (43), and melanomas (31), little is known regarding RIG-I signaling in breast cancers. We used a synthetic agonist to activate the innate immune effector RIG-I in breast cancer cells in culture and in vivo, resulting in decreased tumor growth, decreased metastasis, increased TILs, and induction of tumor cell death via pyroptosis, an immunogenic form of cell death.…”

Section: Discussionmentioning

confidence: 99%

Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers

et al. 2018

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Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell-intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment These findings describe the first in vivo delivery of RIG-I mimetics to tumors, demonstrating a potent immunogenic and therapeutic effect in the context of otherwise poorly immunogenic breast cancers..

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Section: Discussionmentioning

confidence: 99%

Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers

et al. 2018

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“…RIG-I agonists are synthetic RNA oligonucleotides with specific phosphorylation patterns that have shown potent antitumoral effects in preclinical studies [19][20][21][22][23][24] . Interestingly, these agonists not only stimulate anticancer immune responses, but also have a pro-apoptotic effect in cancer cells 19 .…”

Section: The Therapeutic Profile Of Tlr and Rlr Agonistsmentioning

confidence: 99%

Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

Bourquin

Pommier

Hotz

2020

Pharmacological Research

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Cancer immunotherapy has come of age with the advent of immune checkpoint inhibitors. In this article we review how agonists for receptors of the innate immune system, the Toll-like receptors and the RIG-I-like receptors, impact anticancer immune responses. Treatment with these agonists enhances the activity of anticancer effector cells, such as cytotoxic T cells and NK cells, and at the same time blocks the activity of immunosuppressive cell types such as regulatory T cells and myeloid-derived suppressor cells. These compounds also impact the recruitment of immune cells to the tumor. The phenomena of pattern-recognition receptor tolerance and reprogramming and their implications for immunotherapy are discussed. Finally, novel delivery systems that target the immune-stimulating drugs to the tumor or the tumordraining lymph nodes to enhance their efficacy and safety are presented.

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“…13,14 Recently, it was reported that the combination of chemotherapeutics and siRNA targeting MDR genes loaded in nanomaterials can overcome MDR and kill the cancer cells. [15][16][17][18][19] However, the delivery of drug/ gene into tumors strongly relies on the sophisticated design of drug delivery system (DDS), and drug/gene is required to be released in a controlled manner. On the other hand, the biosafety of DDS also remains a concern.…”

Section: Introductionmentioning

confidence: 99%

<p>Self-Assembly Nanoparticles for Overcoming Multidrug Resistance and Imaging-Guided Chemo-Photothermal Synergistic Cancer Therapy</p>

Gao¹,

Chen²,

Fakhri³

et al. 2020

IJN

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Background and Purpose: The development of multiple drug resistance (MDR) to chemotherapy and single modal therapy remains unsatisfied for the eradication of tumor, which are major obstacles in cancer therapy. This novel system with excellent characteristics for inhibition of P-glycoprotein (P-gp), and for near-infrared fluorescence (NIRF) imagingguided chemo-photothermal therapy (PTT), has been identified as a promising way to MDR and achieve synergistic cancer therapy. Methods: In this study, we successfully synthesized a multifunctional theranostic system, which was developed through FDA-approved self-assembling drugs, which contain anticancer drug doxorubicin (Dox), imaging and high photothermal conversion drug indocyanine green (ICG) and P-gp regulator TPGS (the system named T/Dox-ICG). We studied the characterization of T/Dox-ICG NPs, including the TEM, SEM, DLS, UV-vis-NIR, zeta potential, CLSM, in vitro FL imaging, in vitro photothermal effect, in vitro Dox and ICG release. We used CLSM to verify the location of intracellular distribution of Dox in SCG 7901/VCR cells, Western blot was performed to demonstrate the TPGS-mediated inhibition of P-gp. And, the cytotoxicity of materials against SCG 7901/VCR cells was studied by the MTT assay. Results: The TEM showed the T/Dox-ICG NPs had good monodispersity with diameters of 19.03 nm, Dox and ICG could be released constantly from T/Dox-ICG NPs in vitro. In vitro cell experiments demonstrated higher Dox accumulation and retention in the nucleus. Western blot showed TPGS could obviously inhibit the expression of P-gp. In vitro cytotoxicity assay showed more significant cytotoxicity on MDR cells (SCG 7901/VCR) with only 8.75% of cells surviving. Conclusion: MDR cancer therapy indicates that it may be important to develop a safer system that can simultaneously inhibit the drug transporters and monitor the delivery of chemotherapeutic agents, and combination therapy have raised widespread concern on tumor treatment.

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5′-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells

Cited by 23 publications

References 23 publications

Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers

Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers

Harnessing the immune system to fight cancer with Toll-like receptor and RIG-I-like receptor agonists

<p>Self-Assembly Nanoparticles for Overcoming Multidrug Resistance and Imaging-Guided Chemo-Photothermal Synergistic Cancer Therapy</p>

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