Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes.
The association between azacitidine (AZA) and valproic acid (VPA) has shown high response rates in high-risk myelodysplastic syndromes (MDS) cases with unfavorable prognosis. However, little is known about the molecular mechanisms underlying this therapy, and molecular markers useful to monitor the disease and the effect of the treatment are needed. Phosphoinositide-phospholipase C (PI-PLC) β1 is involved in both genetic and epigenetic mechanisms of MDS progression to acute myeloid leukemia. Indeed, AZA as a single agent was able to induce PI-PLCβ1 expression, therefore providing a promising new tool in the evaluation of response to demethylating therapies. In this study, we assessed the efficacy of the combination of AZA and VPA on inducing PI-PLCβ1 expression in high-risk MDS patients. Furthermore, we observed an increase in Cyclin D3 expression, a downstream target of PI-PLCβ1 signaling, therefore suggesting a potential combined activity of AZA and VPA in high-risk MDS in activating PI-PLCβ1 signaling, thus affecting cell proliferation and differentiation. Taken together, our findings might open up new lines of investigations aiming at evaluating the role of the activation of PI-PLCβ1 signaling in the epigenetic therapy, which may also lead to the identification of innovative targets for the epigenetic therapy of high-risk MDS.
Department of Human Anatomical Sciences, University of Bologna, Bologna, Italy.
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MY
Follo
C
C
Finelli
S
S
Mongiorgi
C
C
Clissa
F
F
Chiarini
G
G
Ramazzotti
S
S
Paolini
G
G
Martinelli
A M
AM
Martelli
L
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Cocco
D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001374:Azacitidine / Q000494:pharmacology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D019175:DNA Methylation; D004357:Drug Synergism; D004791:Enzyme Inhibitors; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D054801:Phosphoinositide Phospholipase C / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D014635:Valproic Acid; D054801:Phosphoinositide Phospholipase C; D001374:Azacitidine