Natural compound inducers of immunogenic cell death

Marc Diederich 대한약학회 2019 Archives of Pharmacal Research Vol.42 No.7

Accumulating evidence shows that the anticancerpotential of the immune response that can be activatedby modulation of the immunogenicity of dyingcancer cells. This regulated cell death process is calledimmunogenic cell death (ICD) and constitutes a newinnovating anti-cancer strategy with immune-modulatorypotential thanks to the release of damage-associatedmolecular patterns (DAMPs). Some conventional clinically-used chemotherapeutic drugs, as well as preclinically-investigated compounds of natural origins such asanthracyclines, microtubule-destabilizing agents, cardiacglycosides or hypericin derivatives, possess such animmune-stimulatory function by triggering ICD. Here, wediscuss the effects of ICD inducers on the release ofDAMPs and the activation of corresponding signalingpathways triggering immune recognition. We will discusspotential strategies allowing to overcome resistancemechanisms associated with this treatment approach aswell as co-treatment strategies to overcome the immunosuppressivemicroenvironment. We will highlight thepotential role of metronomic immune modulation as wellas targeted delivery of ICD-inducing compounds withnanoparticles or liposomal formulations to improving theimmunogenicity of ICD inducers aiming at long-termclinical benefits.

Bispecific Antibodies: An Innovative Arsenal to Hunt, Grab and Destroy Cancer Cells

Dicato, Mario,Diederich, Marc Bentham Science 2015 CURRENT PHARMACEUTICAL BIOTECHNOLOGY Vol.16 No.8

<P>Targeted cellular immunotherapy with bifunctional antibodies (bsAbs) has emerged as a promising therapeutic approach for cancer over the last two decades. Progress in antibody engineering has led to the generation of many different types of antibody-derived entities that display at least two binding specificities. Most bsAbs consist of large IgG-like proteins with multiple antigen-binding regions containing Fc parts or smaller entities without Fc. BsAbs have the potential to engage effector cells of the immune system, thereby overcoming some of the immune response escape mechanisms of tumor cells. Preclinical and clinical trials of various bsAb constructs have demonstrated impressive results in terms of immune effector cell retargeting and induction of efficient anti-tumor responses. This review provides an overview of the established bsAbs focusing on improvements in format and design as well as the mechanisms of action of the most promising candidates and describes the results of the most recent clinical studies.</P>

Stress-induced cellular responses in immunogenic cell death: Implications for cancer immunotherapy

Radogna, Flavia,Diederich, Marc Elsevier 2018 Biochemical pharmacology Vol.153 No.-

<P><B>Abstract</B></P> <P>Cancer is evading the host’s defense mechanisms leading to avoidance of immune destruction. During tumor progression, immune-evading cancer cells arise due to selective pressure from the hypoxic and nutrient-deprived microenvironment. Thus, therapies aiming at re-establishing immune destruction of pathological cells constitute innovating anti-cancer strategies. Accumulating evidence suggests that selected conventional chemotherapeutic drugs increase the immunogenicity of stressed and dying cancer cells by triggering a form of cell death called immunogenic cell death (ICD), which is characterized by the release of danger-associated molecular patterns (DAMPs). In this review, we summarize the effects of ICD inducers on DAMP signaling leading to adjuvanticity and antigenicity. We will discuss the associated stress response pathways that cause the release of DAMPs leading to improved immune recognition and their relevance in cancer immunotherapy. Our aim is to highlight the contribution of adaptive immunity to the long-term clinical benefits of anticancer treatments and the properties of immune memory that can protect cancer patients against relapse.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Natural modulators of the hallmarks of immunogenic cell death

Radogna, Flavia,Dicato, Mario,Diederich, Marc Pergamon Press 2019 Biochemical pharmacology Vol.162 No.-

<P><B>Abstract</B></P> <P>Natural compounds act as immunoadjuvants as their therapeutic effects trigger cancer stress response and release of damage-associated molecular patterns (DAMPs). These reactions occur through an increase in the immunogenicity of cancer cells that undergo stress followed by immunogenic cell death (ICD). These processes result in a chemotherapeutic response with a potent immune-mediating reaction. Natural compounds that induce ICD may function as an interesting approach in converting cancer into its own vaccine. However, multiple parameters determine whether a compound can act as an ICD inducer, including the nature of the inducer, the <I>premortem</I> stress pathways, the cell death pathways, the intrinsic antigenicity of the cell, and the potency and availability of an immune cell response. Thus, the identification of hallmarks of ICD is important in determining the prognostic biomarkers for new therapeutic approaches and combination treatments.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Non-Edible Plants as an Attractive Source of Compounds with Chemopreventive Potential

Seungwon Ji,Barbora Orlikova,Marc Diederich 대한암예방학회 2014 Journal of cancer prevention Vol.19 No.1

Cancer remains a lethal disease, and many scientists are currently trying to develop more effective therapies. Natural compounds are potential sources of anti-cancer therapies and are obtained from diverse sources including marine organisms, microorganisms and plants. In this paper, we evaluated natural compounds from non-edible plant sources, which is a neglected area of research despite the promising future of these compounds. In addition, we assessed the function and mechanism of action of these compounds in relation to cancer chemoprevention.

Natural scaffolds in anticancer therapy and precision medicine

Mazumder, Aloran,Cerella, Claudia,Diederich, Marc Elsevier 2018 BIOTECHNOLOGY ADVANCES Vol.36 No.6

<P>The diversity of natural compounds is essential for their mechanism of action. The source, structures and structure activity relationship of natural compounds contributed to the development of new classes of chemotherapy agents for over 40 years. The availability of combinatorial chemistry and high-throughput screening has fueled the challenge to identify novel compounds that mimic natures chemistry and to predict their macromolecular targets. Combining conventional and targeted therapies helped to successfully overcome drug resistance and prolong disease-free survival. Here, we aim to provide an overview of preclinical investigated natural compounds alone and in combination to further improve personalization of cancer treatment.</P>

1,000 Ways to die: natural compounds modulate non-canonical cell death pathways in cancer cells

Orlikova, Barbora,Dicato, Mario,Diederich, Marc Springer-Verlag 2014 Phytochemistry reviews Vol.13 No.1

Anti-cancer effects of naturally derived compounds targeting histone deacetylase 6-related pathways

Lernoux, Manon,Schnekenburger, Michael,Dicato, Mario,Diederich, Marc Elsevier 2018 PHARMACOLOGICAL RESEARCH Vol.129 No.-

<P><B>Abstract</B></P> <P>Alterations of the epigenetic machinery, affecting multiple biological functions, represent a major hallmark enabling the development of tumors. Among epigenetic regulatory proteins, histone deacetylase (HDAC)6 has emerged as an interesting potential therapeutic target towards a variety of diseases including cancer. Accordingly, this isoenzyme regulates many vital cellular regulatory processes and pathways essential to physiological homeostasis, as well as tumor multistep transformation involving initiation, promotion, progression and metastasis. In this review, we will consequently discuss the critical implications of HDAC6 in distinct mechanisms relevant to physiological and cancerous conditions, as well as the anticancer properties of synthetic, natural and natural-derived compounds through the modulation of HDAC6-related pathways.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Histone deacetylase 6 in health and disease.

Seidel, Carole,Schnekenburger, Michael,Dicato, Mario,Diederich, Marc Future Medicine 2015 Epigenomics Vol.7 No.1

<P>Histone deacetylase (HDAC)6 is a member of the class IIb HDAC family. This enzyme is zinc-dependent and mainly localized in the cytoplasm. HDAC6 is a unique isoenzyme with two functional catalytic domains and specific physiological roles. Indeed, HDAC6 deacetylates various substrates including 관-tubulin and HSP90관, and is involved in protein trafficking and degradation, cell shape and migration. Consequently, deregulation of HDAC6 activity was associated to a variety of diseases including cancer, neurodegenerative diseases and pathological autoimmune response. Therefore, HDAC6 represents an interesting potential therapeutic target. In this review, we discuss structural features of this histone deacetylase, regulation of its expression and activity, biological functions, implication in human disease initiation and progression. Finally will describe novel and selective HDAC6 inhibitors.</P>

Coffee provides a natural multitarget pharmacopeia against the hallmarks of cancer

Gaascht, Franç,ois,Dicato, Mario,Diederich, Marc Springer-Verlag 2015 Genes & nutrition Vol.10 No.6