The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding

Sekiba, Kazuma; Otsuka, Motoyuki; Seimiya, Takahiro; Tanaka, Eri; Funato, Kazuyoshi; Miyakawa, Yu; Koike, Kazuhiko

doi:10.1038/s41598-020-72688-y

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…Yet another work showed that inhibition of endogenous AEA degradation enhanced interaction with the tumour immune system. Accordingly, the FAAH inhibitor URB597 suppressed the shedding of the proteins major histocompatibility complex class I polypeptide-related sequence A (MICA) and B (MICB) on the surface of human HCC cells [ 137 ]. Since MICA/B proteins are recognised by cytotoxic lymphocytes expressing the natural killer group 2D (NKG2D) receptor and tumour cells are subsequently eliminated, preventing the shedding of MICA/B proteins can improve antitumour immunity.…”

Section: Interactions With the Immune Systemmentioning

confidence: 99%

Cannabinoids as anticancer drugs: current status of preclinical research

Hinz

Ramer

2022

Br J Cancer

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Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ9-tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies.

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Section: Interactions With the Immune Systemmentioning

confidence: 99%

Cannabinoids as anticancer drugs: current status of preclinical research

Hinz

Ramer

2022

Br J Cancer

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“…Therefore, MMP inhibitors (MMPI) constitute attractive candidates, which is further supported by the finding that mouse prostate tumors engineered to express a shedding-resistant noncleavable MICB did not grow when implanted into SCID mice but treatment of the animals with an NKG2D blocking mAb led to the development of tumors ( 304 ). Several MMPI such as MMPI-I ( 116 , 305 ), MMPI-II ( 117 ), MMPI III ( 117 , 271 ), MMPI-IV ( 306 ), batimastat or BB94 ( 117 , 307 ), GW280264X ( 117 , 301 ), GI1254023X ( 117 ), ilomastat or GM6001 ( 117 , 301 , 308 ), URB597 ( 309 ), periostat or doxycycline ( 310 ) and some ADAM-10 selective inhibitors ( 311 , 312 ) can inhibit MICA/B shedding in vitro , resulting in a heightened cell surface expression of the NKG2DL and an increase in NK cell-mediated cytotoxicity. However, among these compounds, only periostat is currently in clinical trials for different types of tumors ( 313 ).…”

Section: Rational Design Of Combination Therapies That Target the Nkg2d-nkg2dl Axismentioning

confidence: 99%

Leveraging NKG2D Ligands in Immuno-Oncology

2021

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Immune checkpoint inhibitors (ICI) revolutionized the field of immuno-oncology and opened new avenues towards the development of novel assets to achieve durable immune control of cancer. Yet, the presence of tumor immune evasion mechanisms represents a challenge for the development of efficient treatment options. Therefore, combination therapies are taking the center of the stage in immuno-oncology. Such combination therapies should boost anti-tumor immune responses and/or target tumor immune escape mechanisms, especially those created by major players in the tumor microenvironment (TME) such as tumor-associated macrophages (TAM). Natural killer (NK) cells were recently positioned at the forefront of many immunotherapy strategies, and several new approaches are being designed to fully exploit NK cell antitumor potential. One of the most relevant NK cell-activating receptors is NKG2D, a receptor that recognizes 8 different NKG2D ligands (NKG2DL), including MICA and MICB. MICA and MICB are poorly expressed on normal cells but become upregulated on the surface of damaged, transformed or infected cells as a result of post-transcriptional or post-translational mechanisms and intracellular pathways. Their engagement of NKG2D triggers NK cell effector functions. Also, MICA/B are polymorphic and such polymorphism affects functional responses through regulation of their cell-surface expression, intracellular trafficking, shedding of soluble immunosuppressive isoforms, or the affinity of NKG2D interaction. Although immunotherapeutic approaches that target the NKG2D-NKG2DL axis are under investigation, several tumor immune escape mechanisms account for reduced cell surface expression of NKG2DL and contribute to tumor immune escape. Also, NKG2DL polymorphism determines functional NKG2D-dependent responses, thus representing an additional challenge for leveraging NKG2DL in immuno-oncology. In this review, we discuss strategies to boost MICA/B expression and/or inhibit their shedding and propose that combination strategies that target MICA/B with antibodies and strategies aimed at promoting their upregulation on tumor cells or at reprograming TAM into pro-inflammatory macrophages and remodeling of the TME, emerge as frontrunners in immuno-oncology because they may unleash the antitumor effector functions of NK cells and cytotoxic CD8 T cells (CTL). Pursuing several of these pipelines might lead to innovative modalities of immunotherapy for the treatment of a wide range of cancer patients.

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“…Accumulating data suggest that the endocannabinoid system acts as an important regulator of tumour immune defence through multiple mechanisms. For example, the involvement of the endocannabinoid system in the immune response of tumours was recently highlighted by the finding that the FAAH inhibitor URB597 may enhance the immune surveillance of human hepatocellular carcinoma cells [162]. Specifically, URB597 via induction of TIMP-3 expression was found to inhibit proteolytic shedding of the proteins major histocompatibility complex class I polypeptide-related sequence A (MICA) and B (MICB) on the surface of cancer cells, thereby ensuring binding of these proteins to the natural killer group 2D (NKG2D) receptor on the surface of cytolytic lymphocytes and subsequent killing of tumour cells.…”

Section: Effect Of Faah and Magl Inhibition On Tumour-immune Interactionsmentioning

confidence: 99%

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

Ramer

Wittig

Hinz

2021

Cancers

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Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons. Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects. In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread. This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.

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The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding

Cited by 7 publications

References 48 publications

Cannabinoids as anticancer drugs: current status of preclinical research

Cannabinoids as anticancer drugs: current status of preclinical research

Leveraging NKG2D Ligands in Immuno-Oncology

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

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