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>

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>

Plant-derived epigenetic modulators for cancer treatment and prevention

Schnekenburger, M.,Dicato, M.,Diederich, M. Pergamon Press ; Elsevier Science Ltd 2014 BIOTECHNOLOGY ADVANCES Vol.32 No.6

Carcinogenesis is a complex and multistep process that involves the accumulation of successive transformational events driven by genetic mutations and epigenetic alterations that affect major cellular processes and pathways such as proliferation, differentiation, invasion and survival. Massive deregulation of all components of the epigenetic machinery is a hallmark of cancer. These alterations affect normal gene regulation and impede normal cellular processes including cell cycle, DNA repair, cell growth, differentiation and apoptosis. Since epigenetic alterations appear early in cancer development and represent potentially initiating events during carcinogenesis, they are considered as promising targets for anti-cancer interventions by chemopreventive and chemotherapeutic strategies using epigenetically active agents. In this field, plant-derived compounds have shown promise. Here, we will give an overview of plant-derived compounds displaying anticancer properties that interfere with the epigenetic machinery.

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

Roles of Apoptosis and Cellular Senescence in Cancer and Aging

Cerella, Claudia,Grandjenette, Cindy,Dicato, Mario,Diederich, Marc Bentham Science 2016 Current drug targets Vol.17 No.4

<P>Cancer and aging are two similar processes representing the final outcome of time-dependent accumulation of various irreversible dysfunctions, mainly caused by stress-induced DNA and cellular damages. Apoptosis and senescence are two types of cellular response to damages that are altered in both cancer and aging, albeit through different mechanisms. Carcinogenesis is associated with a progressive reduction in the ability of the cells to trigger apoptosis and senescence. In contrast, in aging tissues, there is an increased accumulation of senescent cells, and the nature of apoptosis deregulation varies depending on the tissue. Thus, the prevailing model suggests that apoptosis and cellular senescence function as two essential tumor-suppressor mechanisms, ensuring the health of the individual during early and reproductive stages of life, but become detrimental and promote aging later in life. The recent discovery that various anticancer agents, including canonical inducers of apoptosis, act also as inducers of cellular senescence indicates that pro-senescence strategies may have applications in cancer prevention therapy. Therefore, dissection of the mechanisms mediating the delicate balance between apoptosis and cellular senescence will be beneficial in the therapeutic exploitation of both processes in the development of future anticancer and anti-aging strategies, including minimizing the side effects of such strategies. Here, we provide an overview of the roles of apoptosis and cellular senescence in cancer and aging.</P>

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>

Natural Compounds as Regulators of the Cancer Cell Metabolism

Cerella, Claudia,Radogna, Flavia,Dicato, Mario,Diederich, Marc Hindawi Publishing Corporation 2013 International journal of cell biology Vol.2013 No.-

<P>Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration) and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism.</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

Autophagy as a pharmacological target in hematopoiesis and hematological disorders

Orsini, Marion,Morceau, Franck,Dicato, Mario,Diederich, Marc Elsevier 2018 Biochemical pharmacology Vol.152 No.-

<P><B>Abstract</B></P> <P>Autophagy is involved in many cellular processes, including cell homeostasis, cell death/survival balance and differentiation. Autophagy is essential for hematopoietic stem cell survival, quiescence, activation and differentiation. The deregulation of this process is associated with numerous hematological disorders and pathologies, including cancers. Thus, the use of autophagy modulators to induce or inhibit autophagy emerges as a potential therapeutic approach for treating these diseases and could be particularly interesting for differentiation therapy of leukemia cells. This review presents therapeutic strategies and pharmacological agents in the context of hematological disorders. The pros and cons of autophagy modulators in therapy will also be discussed.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>