Natural compounds and pharmaceuticals reprogram leukemia cell differentiation pathways

Morceau, F.,Chateauvieux, S.,Orsini, M.,Trecul, A.,Dicato, M.,Diederich, M. Pergamon Press ; Elsevier Science Ltd 2015 BIOTECHNOLOGY ADVANCES Vol.33 No.6

In addition to apoptosis resistance and cell proliferation capacities, the undifferentiated state also characterizes most cancer cells, especially leukemia cells. Cell differentiation is a multifaceted process that depends on complex regulatory networks that involve transcriptional, post-transcriptional and epigenetic regulation of gene expression. The time- and spatially-dependent expression of lineage-specific genes and genes that control cell growth and cell death is implicated in the process of maturation. The induction of cancer cell differentiation is considered an alternative approach to elicit cell death and proliferation arrest. Differentiation therapy has mainly been developed to treat acute myeloid leukemia, notably with all-trans retinoic acid (ATRA). Numerous molecules from diverse natural or synthetic origins are effective alone or in association with ATRA in both in vitro and in vivo experiments. During the last two decades, pharmaceuticals and natural compounds with various chemical structures, including alkaloids, flavonoids and polyphenols, were identified as potential differentiating agents of hematopoietic pathways and osteogenesis.

Long and Short Non-Coding RNAs as Regulators of Hematopoietic Differentiation

Morceau, Franck,Chateauvieux, Sé,bastien,Gaigneaux, Anthoula,Dicato, Mario,Diederich, Marc Molecular Diversity Preservation International (MD 2013 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.14 No.7

<P>Genomic analyses estimated that the proportion of the genome encoding proteins corresponds to approximately 1.5%, while at least 66% are transcribed, suggesting that many non-coding DNA-regions generate non-coding RNAs (ncRNAs). The relevance of these ncRNAs in biological, physiological as well as in pathological processes increased over the last two decades with the understanding of their implication in complex regulatory networks. This review particularly focuses on the involvement of two large families of ncRNAs, namely microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of hematopoiesis. To date, miRNAs have been widely studied, leading to a wealth of data about processing, regulation and mechanisms of action and more specifically, their involvement in hematopoietic differentiation. Notably, the interaction of miRNAs with the regulatory network of transcription factors is well documented whereas roles, regulation and mechanisms of lncRNAs remain largely unexplored in hematopoiesis; this review gathers current data about lncRNAs as well as both potential and confirmed roles in normal and pathological hematopoiesis.</P>

Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1

De Bosscher, Karolien,Beck, Ilse M.,Dejager, Lien,Bougarne, Nadia,Gaigneaux, Anthoula,Chateauvieux, Sé,bastien,Ratman, Dariusz,Bracke, Marc,Tavernier, Jan,Vanden Berghe, Wim,Libert, Claude,Diede Springer Basel 2014 Cellular and molecular life sciences Vol.71 No.1

<P>Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene <I>c</I>-<I>jun</I>, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile.</P><P><B>Electronic supplementary material</B></P><P>The online version of this article (doi:10.1007/s00018-013-1367-4) contains supplementary material, which is available to authorized users.</P>

Polyphenol tri-vanillic ester 13c inhibits P-JAK2V617F and Bcr-Abl oncokinase expression in correlation with STAT3/STAT5 inactivation and apoptosis induction in human leukemia cells

Trecul, A.,Morceau, F.,Gaigneaux, A.,Orsini, M.,Chateauvieux, S.,Grandjenette, C.,Dicato, M.,Diederich, M. Elsevier Science Ireland 2013 Cancer letters Vol.340 No.1

Constitutive activity of kinases has been reported in many types of cancers, so that inhibition of ''onco-kinases'' became a validated anti-cancer strategy. We found that the polyphenol 13c, a tri-vanillate derivative, inhibited kinase phosphorylation in leukemia cells. P-JAK2, P-Src and P-PI3Kp85 inhibition occurred independently of phosphatase involvement in JAK2V617F expressing HEL cells while 13c inhibited Bcr-Abl expression without inhibition of phosphorylation in chronic myelogenous leukemia cell lines (K562, MEG-01). In correlation with kinase inhibition, 13c abolished constitutive P-STAT3/P-STAT5 expression, down-regulated Mcl-1 and c-Myc gene expression and induced apoptosis. Altogether, polyphenol 13c displays potential antitumor activities by affecting onco-kinases and STAT activities.

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>

The dialkyl resorcinol stemphol disrupts calcium homeostasis to trigger programmed immunogenic necrosis in cancer

Ji, Seungwon,Lee, Jin-Young,Schrö,r, Jan,Mazumder, Aloran,Jang, Dong Man,Chateauvieux, Sé,bastien,Schnekenburger, Michael,Hong, Che Ry,Christov, Christo,Kang, Hyoung Jin,Lee, Youngjo,Han, By Elsevier 2018 Cancer letters Vol.416 No.-

<P><B>Abstract</B></P> <P>Stemphol (STP) is a novel druggable phytotoxin triggering mixed apoptotic and non-apoptotic necrotic-like cell death in human acute myeloid leukemia (AML). Use of several chemical inhibitors highlighted that STP-induced non-canonical programmed cell death was Ca<SUP>2+</SUP>-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca<SUP>2+</SUP> levels and computational docking confirmed binding of STP within the thapsigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca<SUP>2+</SUP>-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca<SUP>2+</SUP> accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron microscopy. Confocal fluorescent microscopy allowed identifying mitochondrial Ca<SUP>2+</SUP> overload as initiator of STP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that STP-induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly, the translational immunogenic potential of STP was validated by HMGB1 release of STP-treated AML patient cells. STP reduced colony and <I>in vivo</I> tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Stemphol induces cell death by disrupting calcium homeostasis. </LI> <LI> Stemphol induces necrosis by mediating mPTP opening. </LI> <LI> Stemphol triggers immunogenic cell death markers ER stress and HMGB1 release. </LI> <LI> Stemphol impairs development of leukemia patient-derived zebrafish xenografts. </LI> </UL> </P>