@article {3581, title = {Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3.}, journal = {Oncotarget}, volume = {5}, year = {2014}, month = {2014 Jun 30}, pages = {4347-60}, abstract = {

The anti-leukemic activity of the mitochondria-targeting small molecule sodium dichloroacetate (DCA), used alone and in association with the small molecule inhibitor of the p53/MDM2 interaction Nutlin-3, was analyzed in primary B-chronic lymphocytic leukemia (B-CLL) samples (n=22), normal peripheral blood cells (n=10) and in p53wild-type EHEB, JVM-2, JVM-3 B lymphoblastoid cell lines. DCA exhibited a dose-dependent anti-leukemic activity in both primary B-CLL and B leukemic cell lines with a functional p53 status and showed a synergistic cytotoxic activity when used in combination with Nutlin-3. At the molecular level, DCA positively regulated p53 activity, as documented by post-transcriptional modifications of p53 protein and synergized with Nutlin-3 in increasing the expression of the p53-target genes MDM2, PUMA, TIGAR and in particular p21. The potential role of p21 in mediating the DCA+Nutlin-3 anti-leukemic activity was underscored in knocking-down experiments. Indeed, transfection of leukemic cells with p21 siRNAs significantly decreased the DCA+Nutlin-3-induced cytotoxicity. Taken together, our data emphasize that DCA is a molecule that merits to be further evaluated as a chemotherapeutic agent for B-CLL, likely in combination with other therapeutic compounds.

}, keywords = {Aged, Aged, 80 and over, Dichloroacetic Acid, Drug Synergism, Female, Humans, Imidazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Middle Aged, Piperazines, Tumor Suppressor Protein p53}, issn = {1949-2553}, author = {Agnoletto, Chiara and Melloni, Elisabetta and Casciano, Fabio and Rigolin, Gian Matteo and Rimondi, Erika and Celeghini, Claudio and Brunelli, Laura and Cuneo, Antonio and Secchiero, Paola and Zauli, Giorgio} } @article {1903, title = {SOCS1 is significantly up-regulated in Nutlin-3-treated p53wild-type B chronic lymphocytic leukemia (B-CLL) samples and shows an inverse correlation with miR-155.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Dec}, pages = {2403-6}, abstract = {

The basal SOCS1 mRNA levels were significantly lower in p53(mutated) BJAB and MAVER leukemic cell lines with respect to p53(wild-type) SKW6.4 and JVM-2 leukemic cell lines, p53(wild-type) primary B chronic lymphocytic leukemia (B-CLL) cells and primary normal peripheral blood mononuclear cells (PBMC). Moreover, the MDM2 small molecule inhibitor Nutlin-3 significantly increased the levels of SOCS1 mRNA in both primary p53(wild-type) B-CLL cells as well as in p53(wild-type) B leukemic cell lines, but not in p53(mutated) B leukemic cell lines nor in primary PBMC. Of note, a significant inverse correlation was observed between SOCS1 mRNA and miR-155 levels in Nutlin-3-treated primary B-CLL cells and PBMC, suggesting that the miRNA-155/SOCS1 axis represents a potentially important therapeutic target of Nutlin-3 in B-CLL.

}, keywords = {Cell Line, Tumor, Cells, Cultured, Down-Regulation, Humans, Imidazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Leukocytes, Mononuclear, MicroRNAs, Piperazines, Suppressor of Cytokine Signaling Proteins, Tumor Suppressor Protein p53, Up-Regulation}, issn = {1573-0646}, doi = {10.1007/s10637-011-9786-2}, author = {di Iasio, Maria Grazia and Norcio, Alessia and Melloni, Elisabetta and Zauli, Giorgio} } @article {1926, title = {The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.}, journal = {Haematologica}, volume = {97}, year = {2012}, month = {2012 Nov}, pages = {1722-30}, abstract = {

BACKGROUND: Both the multi-kinase inhibitor sorafenib and the small molecule inhibitor of the MDM2/p53 interaction, nutlin-3, used alone, have shown promising anti-leukemic activity in acute myeloid leukemia cells. Thus, in this study we investigated the effect of the combination of sorafenib plus nutlin-3 in acute myeloid leukemia.

DESIGN AND METHODS: Primary acute myeloid leukemia blasts (n=13) and FLT3(wild-type)/p53(wild-type) (OCI-AML3), FLT3(mutated)/p53(wild-type) (MOLM), FLT3(mutated)/p53(mutated) (MV4-11), FLT3(wild-type)/p53(deleted) (HL60) or FLT3(wild-type)/p53(mutated) (NB4) acute myeloid cell lines were exposed to sorafenib, used alone or in association with nutlin-3 at a 1:1 ratio, in a range of clinically achievable concentrations (1-10 μM). Induction of apoptosis and autophagy was evaluated by transmission electron microscopy and by specific flow cytometry analyses. The levels of Mcl-1, p53 and Bak proteins were analyzed by western blotting. Knock-down of Bax and Bak gene expression was performed in transfection experiments with specific short interfering RNA.

RESULTS: The sorafenib+nutlin-3 drug combination exhibits synergistic cytotoxicity in primary acute myeloid leukemia blasts and in acute myeloid leukemia cell lines with maximal cytotoxicity in FLT3(mutated) MV4-11 and MOLM, followed by the FLT3(wild-type) OCI-AML3, HL60 and NB4 cell lines. The cytotoxic activity of sorafenib+nutlin-3 was characterized by an increase of both apoptosis and autophagy. Moreover, Bax and Bak showed prominent roles in mediating the decrease of cell viability in response to the drug combination in p53(wild-type) OCI-AML3 and p53(deleted) HL-60 cells, respectively, as demonstrated in transfection experiments performed with specific short interfering RNA.

CONCLUSIONS: Our data demonstrate that acute myeloid leukemia cells show a variable but overall good susceptibility to the innovative therapeutic combination of sorafenib+nutlin-3, which differentially involves the pro-apoptotic Bcl-2 family members Bax and Bak in p53(wild-type) and p53(deleted) cells.

}, keywords = {Antineoplastic Agents, Drug Synergism, Female, fms-Like Tyrosine Kinase 3, HL-60 Cells, Humans, Imidazoles, Leukemia, Myeloid, Acute, Male, Niacinamide, Phenylurea Compounds, Piperazines, Tumor Suppressor Protein p53}, issn = {1592-8721}, doi = {10.3324/haematol.2012.062083}, author = {Zauli, Giorgio and Celeghini, Claudio and Melloni, Elisabetta and Voltan, Rebecca and Ongari, Manuele and Tiribelli, Mario and di Iasio, Maria Grazia and Lanza, Francesco and Secchiero, Paola} }