Natural compounds and pharmaceuticals reprogram leukemia cell differentiation pathways.

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.

Valproic acid regulates erythro-megakaryocytic differentiation through the modulation of transcription factors and microRNA regulatory micro-networks.

Valproic acid (VPA) exhibits important pharmacological properties but has been reported to trigger side effects, notably on the hematological system. We previously reported that VPA affects hematopoietic homeostasis by inhibiting erythroid differentiation and promoting myeloid and megakaryocyte differentiation. Here, we analyzed the effect of VPA on regulatory factors involved in erythro-megakaryocytic differentiation pathways, including transcription factors and microRNAs (miRs). We demonstrate that VPA inhibited erythroid differentiation in erythropoietin (Epo)-stimulated TF1 leukemia cells and CD34(+)/hematopoietic stem cells (HSCs) and in aclacinomycin-(Acla)-treated K562 cells. Mir-144/451 gene expression was decreased in all erythroid and megakaryocyte models in correlation with GATA-1 inhibition. In Epo-stimulated CD34(+)/HSCs, VPA induced the expression of the ETS family transcription factors PU.1, ETS-1, GABP-α, Fli-1 and GATA-2, which are all known to be negative regulators of erythropoiesis, while it promoted the megakaryocytic pathway. PU.1 and ETS-1 expression were induced in correlation with miR-155 inhibition; however, the GATA-1/PU.1 interaction was promoted. Using megakaryoblastic Meg-01 cells, we demonstrated that VPA induced megakaryocyte morphological features and CD61 expression. GATA-2 and miR-27a expression were increased in correlation with a decrease in RUNX1 mRNA expression, suggesting megakaryocyte differentiation. Finally, by using valpromide and the Class I HDACi MS-275, we validated that the well-described HDACi activity of VPA is not required in the inhibitory effect on erythropoiesis. Overall, this report shows that VPA modulates the erythro-megakaryocytic differentiation program through regulatory micro-networks involving GATA and ETS transcription factors and miRNAs, notably the GATA-1/miR-144/451 axis.

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.

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.

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network.

Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor- and cytokine-membrane receptors including interferon and interleukin, or by non-receptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.