Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis

Dong, Yunhui; Wang, Suhua; Wang, Chunting; Li, Zihua; Ma, Yao; Liu, Gang

doi:10.1021/acs.jmedchem.6b01704

Cited by 28 publications

(32 citation statements)

References 23 publications

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“…The role of NOD2 in cancer immunity is controversially reported 12,45,46 , and it varies depending on the types of cancer. NOD2 is an important component of the innate immune system and it constitutes an interesting regulatory target in terms of strengthening the immune response against cancer cells.…”

Section: Discussionmentioning

confidence: 99%

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Qiu

Sun

et al. 2020

Cell Death Dis

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Nucleotide binding oligomerization domain 2 (NOD2) is a recognized innate immune sensor which can initiate potent immune response against pathogens. Many innate immune sensors have been reported to be of great importance in carcinogenesis. However, the role of NOD2 in cancer is not well understood. Here we investigated the role of NOD2 in the development of hepatocellular carcinoma (HCC). We demonstrated that NOD2 deficiency promoted hepatocarcinogenesis in N-nitrosodiethylamine (DEN)/carbon tetrachloride (CCl 4) induced HCC mice model and xenograft tumor model. In vitro investigation showed that NOD2 acted as a tumor suppressor and inhibited proliferation, colony formation and invasion of HCC cells. Clinical investigation showed that NOD2 expression was completely lost or significantly downregulated in clinical HCC tissues, and loss of NOD2 expression was significantly correlated with advanced disease stages. Further investigation showed that NOD2 exerted its anti-tumor effect through activating adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, and NOD2 significantly enhanced the sensitivity of HCC cells to sorafenib, lenvatinib and 5-FU treatment through activating AMPK pathway induced apoptosis. Moreover, we demonstrated that NOD2 activated AMPK pathway by directly binding with AMPKα-LKB1 complex, which led to autophagy-mediated apoptosis of HCC cells. Altogether, this study showed that NOD2 acted as a tumor suppressor as well as a chemotherapeutic regulator in HCC cells by directly activating AMPK pathway, which indicated a potential therapeutic strategy for HCC treatment by upregulating NOD2-AMPK signaling axis.

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Section: Discussionmentioning

confidence: 99%

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Qiu

Sun

et al. 2020

Cell Death Dis

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“…It was therefore proposed that, in mice, NOD2 was activated mainly by DAMPs generated as a result of the treatment with PTX and, in turn, resulted in TME remodeling, chemoresistance, and metastasis. Furthermore, it was suggested that 37 prevented the establishment of an inflammatory TME by blocking DAMPs and therefore sensitized the chemotherapeutic response of PTX . Recently, Wang et al identified a heterocyclic 1,4‐benzodiazepine‐2,5‐dione derivative 38 as a dual NOD1/NOD2 antagonist that, remarkably, enhanced the antitumor efficacy of PTX.…”

Section: Nod Ligands As Anticancer Agentsmentioning

confidence: 99%

“…Furthermore, it was suggested that 37 prevented the establishment of an inflammatory TME by blocking DAMPs and therefore sensitized the chemotherapeutic response of PTX. 217 Recently, Wang et al 218 identified a heterocyclic 1,4-benzodiazepine-2,5-dione derivative 38 as a dual NOD1/NOD2 antagonist that, remarkably, enhanced the antitumor efficacy of PTX. Concomitant administration of multiple injections of 38 (20 mg/kg) and PTX (12 mg/kg) into mice beginning one day after LLC tumor cell inoculation resulted in a substantial tumor weight inhibition (67%) whereas treatment with PTX (34%) or 38 (10%) alone exerted no significant beneficial effect.…”

mentioning

confidence: 99%

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

Nabergoj

Mlinarič-Raščan

Jakopin

2018

Medicinal Research Reviews

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In the last decade, cancer immunotherapy has emerged as an effective alternative to traditional therapies such as chemotherapy and radiation. In contrast to the latter, cancer immunotherapy has the potential to distinguish between cancer and healthy cells, and thus to avoid severe and intolerable side‐effects, since the cancer cells are effectively eliminated by stimulated immune cells. The cytosolic nucleotide‐binding oligomerization domains 1 and 2 receptors (NOD1 and NOD2) are important components of the innate immune system and constitute interesting targets in terms of strengthening the immune response against cancer cells. Many NOD ligands have been synthesized, in particular NOD2 agonists that exhibit favorable immunostimulatory and anticancer activity. Among them, mifamurtide has already been approved in Europe by the European Medicine Agency for treating patients with osteosarcoma in combination with chemotherapy after complete surgical removal of the primary tumor. This review is focused on NOD receptors as promising targets in cancer immunotherapy as well as summarizing current knowledge of the various NOD ligands exhibiting antitumor and even antimetastatic activity in vitro and in vivo.

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“…[58,59] Desmuramyl peptide-based agents can be used for immunotherapy in the treatment of cancer, for example DMP paclitaxel conjugates. [60,61] Preparation of appropriate formulations acting as delivery systems represents another approach for the design of efficient adjuvants. Strength and mechanisms of immunostimulation induced by nanocarrier vaccines depend on chemical composition, particle size and homogeneity, charge, nature and location of antigens and/or adjuvants within the delivery systems.…”

Section: Future Perspectivementioning

confidence: 99%

Advances in Desmuramyl Peptide Research

Ribić

Paurević

Tomić

2019

Croat. chem. acta (Online)

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Immune adjuvants are added to vaccines in order to enhance the immune response to an antigen. Muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine, is the smallest structural unit of peptidoglycans showing the immunostimulating activity. Muramyl dipeptide analogues without the hydrophilic N-acetylmuramyl moiety are called desmuramyl peptides. Here, we provide review of desmuramyl peptides which were synthesized in order to improve the pharmacological properties of parent muramyl dipeptide, including our results regarding adamantane containing derivatives. Approach for future design of novel immunostimulators based on multiple pathogen recognition receptor activation was also considered.

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Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis

Cited by 28 publications

References 23 publications

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

NOD2 inhibits tumorigenesis and increases chemosensitivity of hepatocellular carcinoma by targeting AMPK pathway

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

Advances in Desmuramyl Peptide Research

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