Bcl-2 protein family expression pattern determines synergistic pro-apoptotic effects of BH3 mimetics with hemisynthetic cardiac glycoside UNBS1450 in acute myeloid leukemia

Cerella, C,Gaigneaux, A,Mazumder, A,Lee, J-Y,Saland, E,Radogna, F,Farge, T,Vergez, F,Ré,cher, C,Sarry, J-E,Kim, K-W,Shin, H Y,Dicato, M,Diederich, M Nature Publishing Group 2017 Leukemia Vol.31 No.3

From nature to bedside: Pro-survival and cell death mechanisms as therapeutic targets in cancer treatment

Cerella, C.,Teiten, M.H.,Radogna, F.,Dicato, M.,Diederich, M. Pergamon Press ; Elsevier Science Ltd 2014 BIOTECHNOLOGY ADVANCES Vol.32 No.6

Cell death is an important physiological regulator during development, tissue homeostasis and stress response but it is also a protective tumor suppressive mechanism. Tumor cells almost universally acquire the ability to evade cell death pathways that in normal cells act as a protective mechanism to remove damaged cells. As a result, a population of death-resistant cells with accumulating genetic and epigenetic abnormalities contributes to malignant transformation. Any alteration of the homeostatic balance between survival and death is therefore a critical factor in carcinogenesis. Several forms of cell death exist and cross talk among them is emerging; however, we still miss many molecular details. It becomes essential to revisit the role of each type of cell death to understand interconnections existing between different cell death pathways as well as the network of their mediators to eventually develop new effective strategies to kill cancer cells. More specifically, new therapies based on compounds selectively triggering apoptosis, necrosis or autophagy recently became both appealing and challenging. Despite the rather clear classification of the different cell death modalities according to morphological criteria and the attempt to describe them with distinct signaling pathways, the reality reveals a complex interplay between apoptosis, regulated necrosis and autophagy involving a heterogeneous mix of molecular mediators. Nature, presenting an almost endless plenitude of bioactive scaffolds, can efficiently contribute compounds that allow deciphering the intricate pathways of cell death pathways and thus eventually contribute to selectively target cancer-type specific pathways in an attempt to personalize cancer patient treatment depending on cancer death pathway specificities. The aim of this review is to provide first an overview of molecular cell death specificities and to highlight how compounds of natural origins, with or without hemisynthetic modifications, target unique thanatotic molecular constellations.

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>

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>

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>

Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in neuroblastoma

Radogna, F,Cerella, C,Gaigneaux, A,Christov, C,Dicato, M,Diederich, M Macmillan Publishers Limited 2016 Oncogene Vol.35 No.29

<P>A limiting factor in the therapeutic outcome of children with high-risk neuroblastoma is the intrinsic and acquired resistance to common chemotherapeutic treatments. Here we investigated the molecular mechanisms by which the hemisynthetic cardiac glycoside UNBS1450 overcomes this limitation and induces differential cell death modalities in both neuroblastic and stromal neuroblastoma through stimulation of a cell-type-specific autophagic response eventually leading to apoptosis or necroptosis. In neuroblastic SH-SY5Y cells, we observed a time-dependent production of reactive oxygen species that affects lysosomal integrity inducing lysosome-associated membrane protein 2 degradation and cathepsin B and L activation. Subsequent mitochondrial membrane depolarization and accumulation of mitochondria in phagophores occurred after 8h of UNBS1450 treatment. Results were confirmed by mitochondrial mass analysis, electron microscopy and co-localization of mitochondria with GFP-LC3, suggesting the impaired clearance of damaged mitochondria. Thus, a stress-induced defective autophagic flux and the subsequent lack of clearance of damaged mitochondria sensitized SH-SY5Y cells to UNBS1450-induced apoptosis. Inhibition of autophagy with small inhibitory RNAs against ATG5, ATG7 and Beclin-1 protected SH-SY5Y cells against the cytotoxic effect of UNBS1450 by inhibiting apoptosis. In contrast, autophagy progression towards the catabolic state was observed in stromal SK-N-AS cells: here reactive oxygen species (ROS) generation remained undetectable preserving intact lysosomes and engulfing damaged mitochondria after UNBS1450 treatment. Moreover, autophagy inhibition determined sensitization of SK-N-AS to apoptosis. We identified efficient mitophagy as the key mechanism leading to failure of activation of the apoptotic pathway that increased resistance of SK-N-AS to UNBS1450, triggering rather necroptosis at higher doses. Altogether we characterize here the differential modulation of ROS and mitophagy as a main determinant of neuroblastoma resistance with potential relevance for personalized anticancer therapeutic approaches.</P>

Biotinylation enhances the anticancer effects of 15d-PGJ2 against breast cancer cells

Colin, C.,Meyer, M.,Cerella, C.,Kleinclauss, A.,Monard, G.,Boisbrun, M.,Diederich, M.,Flament, S.,Grillier-Vuissoz, I.,Kuntz, S. Spandidos Publications 2018 International journal of oncology Vol.52 No.6

Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer

Lee, Jin-Young,Talhi, Oualid,Jang, Dongman,Cerella, Claudia,Gaigneaux, Anthoula,Kim, Kyu-Won,Lee, Jung Weon,Dicato, Mario,Bachari, Khaldoun,Han, Byung Woo,Silva, Artur M.S.,Orlikova, Barbora,Diederich Elsevier 2018 Cancer letters Vol.416 No.-

<P><B>Abstract</B></P> <P>Coumarins are natural compounds with antioxidant, anti-inflammatory and anti-cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1-targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as <I>in vivo</I> by zebrafish xenografts.</P>

Hydroxycoumarin OT-55 kills CML cells alone or in synergy with imatinib or Synribo: Involvement of ER stress and DAMP release

Mazumder, Aloran,Lee, Jin-Young,Talhi, Oualid,Cerella, Claudia,Chateauvieux, Sé,bastien,Gaigneaux, Anthoula,Hong, Che Ry,Kang, Hyoung Jin,Lee, Youngjo,Kim, Kyu-Won,Kim, Dong-Wook,Shin, Hee-Young Elsevier 2018 Cancer letters Vol.438 No.-

<P><B>Abstract</B></P> <P>We synthetized and investigated the anti-leukemic potential of the novel cytostatic bis(4-hydroxycoumarin) derivative OT-55 which complied with the Lipinski's rule of 5 and induced differential toxicity in various chronic myeloid leukemia (CML) cell models. OT-55 triggered ER stress leading to canonical, caspase-dependent apoptosis and release of danger associated molecular patterns. Consequently, OT-55 promoted phagocytosis of OT-55-treated CML cells by both murine and human monocyte-derived macrophages. Moreover, OT-55 inhibited tumor necrosis factor α-induced activation of nuclear factor-кB and produced synergistic effects when used in combination with imatinib to inhibit colony formation <I>in vitro</I> and Bcr-Abl<SUP>+</SUP> patient blast xenograft growth in zebrafish. Furthermore, OT-55 synergized with omacetaxine in imatinib-resistant KBM-5 R cells to inhibit the expression of Mcl-1, triggering apoptosis. In imatinib-resistant K562 R cells, OT-55 triggered necrosis and blocked tumor formation in zebrafish in combination with omacetaxine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> OT-55 inhibits cell proliferation and viability in CML. </LI> <LI> OT-55 induces ER stress, ecto-CRT, ecto-ERp57, ATP and HMGB1 elease leading to immunogenic cell death. </LI> <LI> OT-55-treated CML cells are phagocytosed by macrophages. </LI> <LI> OT-55 synergizes with imatinib in CML. </LI> <LI> OT-55 synergizes with Synribo in Bcr-Abl mutated CML. </LI> </UL> </P>

2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells.

Sobolewski, Cyril,Rhim, Jiyun,Legrand, Noé,mie,Muller, Florian,Cerella, Claudia,Mack, Fabienne,Chateauvieux, Sé,bastien,Kim, Jeoung-Gyun,Yoon, Ah-Young,Kim, Kyu-Won,Dicato, Mario,Diederich American Society for Pharmacology and Experimental 2015 The Journal of Pharmacology and Experimental Thera Vol.355 No.2

<P>Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies.</P>