@article {8097, title = {Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity.}, journal = {J Med Chem}, year = {2015}, month = {2015 Dec 23}, abstract = {

The mitochondrial kinase inhibitor dichloroacetate (DCA) has recently received attention in oncology due to its ability to target glycolysis. However, DCA molecule exhibits poor bioavailability and cellular uptake with limited ability to reach its target mitochondria. To overcome these biases, we have synthesized novel DCA-loaded compounds. The selection of the most promising therapeutic molecule was evaluated by combining in vitro assays, to test the antitumoral potential on leukemic cells, and a preliminary characterization of the molecule stability in vivo, in mice. Among the newly synthesized compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it exhibited enhanced (>30-fold) in vitro antitumor activity with respect to DCA and increased in vivo stability. On the basis of these results, we believe that compound 10 should be considered for further preclinical evaluations for the treatment of cancers and/or other diseases characterized by altered metabolic origin.

}, issn = {1520-4804}, doi = {10.1021/acs.jmedchem.5b01165}, author = {Trapella, Claudio and Voltan, Rebecca and Melloni, Elisabetta and Tisato, Veronica and Celeghini, Claudio and Bianco, Sara and Fantinati, Anna and Salvadori, Severo and Guerrini, Remo and Secchiero, Paola and Zauli, Giorgio} } @article {1739, title = {Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway.}, journal = {Clin Cancer Res}, volume = {17}, year = {2011}, month = {2011 Feb 15}, pages = {762-70}, abstract = {

PURPOSE: To analyze the effect of the combination of Dasatinib, a multikinase inhibitor, plus Nutlin-3, a nongenotoxic activator of the p53 pathway, in primary B chronic lymphocytic leukemia (B-CLL) patient samples and B leukemic cell line models.

EXPERIMENTAL DESIGN: The induction of cytotoxicity was evaluated in both primary B-CLL cell samples (n = 20) and in p53(wild-type) (EHEB, JVM-2) and p53(deleted/mutated) (MEC-2, BJAB) B leukemic cell lines. The role of Akt in modulating leukemic cell survival/apoptosis in response to Dasatinib or Dasatinib + Nutlin-3 was documented by functional experiments carried out using specific pharmacological inhibitors and by overexpression of membrane-targeted constitutively active form of Akt.

RESULTS: The combination of Dasatinib + Nutlin-3 exhibited a synergistic cytotoxicity in the majority (19 out of 20) of B-CLL samples, including patients carrying 17p- (n = 4), and in both p53(wild-type) and p53(deleted/mutated) B leukemic cell lines. At the molecular level, Dasatinib significantly counteracted the Nutlin-3-mediated induction of the p53 transcriptional targets MDM2 and p21 observed in p53(wild-type) leukemic cells. Conversely, Nutlin-3 did not interfere with the ability of Dasatinib to decrease the phosphorylation levels of ERK1/2, p38/MAPK, and Akt in both p53(wild-type) and p53(deleted/mutated) B leukemic cell lines. A critical role of Akt downregulation in mediating the antileukemic activity of Dasatinib and Dasatinib + Nutlin-3 was demonstrated in experiments carried out by specifically modulating the Akt pathway.

CONCLUSIONS: These findings suggest that Dasatinib + Nutlin-3 might represent an innovative therapeutic combination for both p53(wild-type) and p53(deleted/mutated) B-CLL.

}, keywords = {Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Survival, Down-Regulation, Drug Synergism, Humans, Imidazoles, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Piperazines, Protein Kinase Inhibitors, Protein Kinases, Proto-Oncogene Proteins c-akt, Pyrimidines, Thiazoles, Transcription, Genetic, Tumor Suppressor Protein p53}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-10-2572}, author = {Zauli, Giorgio and Voltan, Rebecca and Bosco, Raffaella and Melloni, Elisabetta and Marmiroli, Sandra and Rigolin, Gian Matteo and Cuneo, Antonio and Secchiero, Paola} }