benzofurans and Leukemia--Myeloid--Acute

Histone deacetylase (HDAC) inhibitor abexinostat is under investigation for the treatment of various cancers. Epigenetic changes including aberrant HDAC activity are associated with cancers, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). In this phase 1 dose-escalation study, 17 patients with relapsed/refractory higher-risk MDS, AML, or ALL received oral abexinostat (60, 80 [starting dose], 100, or 120 mg) twice daily (bid) on Days 1-14 of 21-day cycles. The most common treatment-related grade ≥3 adverse events were thrombocytopenia (29%) and neutropenia (24%), none of which led to discontinuation. Maximum-tolerated dose was not reached. Of 12 evaluable patients, best response was stable disease in 1 patient. This study was closed due to limited clinical benefit. Future development of oral abexinostat 100 mg bid in patients with MDS, AML, or ALL should focus on combination regimens. ISRCTN registry: 99680465.

Topics: Adult; Aged; Benzofurans; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Retreatment; Treatment Outcome; Young Adult

Acute myeloid leukemia (AML) is a heterogeneous malignancy of hematopoietic stem cells with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Thus, new therapeutic agents are urgently needed in order to prolong the disease-free survival of AML patients in clinic. Here, we report that BBI608 is highly active against diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, as well as effective in vivo in AML xenograft models. Meanwhile, the anti-AML property of BBI608 is closely associated with the inhibition of Stat3 pathway and induction of DNA damage. Of note, BBI608 combined with Bcl-2 inhibitor (i.e., ABT-199) exerts a significantly enhanced anti-leukemia effect in BBI608-resistant cell line Kasumi-1. Together, the present findings suggest that BBI608 might represent a potential candidate agent for AML treatment.

Topics: Adolescent; Adult; Aged; Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Proliferation; DNA Damage; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; G1 Phase Cell Cycle Checkpoints; Humans; Leukemia, Myeloid, Acute; Male; Membrane Potential, Mitochondrial; Mice; Middle Aged; Naphthoquinones; Resting Phase, Cell Cycle; STAT3 Transcription Factor; Time Factors; Xenograft Model Antitumor Assays; Young Adult

Acute myelogenous leukemia (AML) is a clinically heterogeneous disease that is frequently associated with relapse and a poor prognosis. Among the various subtypes, AML with the monosomal karyotype (AML-MK) has an extremely unfavorable prognosis. We performed screening to identify antitumor compounds that are capable of inducing apoptosis in primary leukemia cells harboring the AML-MK karyotype and identified a naturally occurring stilbene, Gnetin-C, with potent anti-tumor activities against AML cells from patients with various cytogenetic abnormalities, including patients with the AML-MK karyotype. Gnetin-C simultaneously inhibits the ERK1/2 and the AKT/mTOR pathways, two signals that are essential for the survival of leukemia cells. A combination of Gnetin-C with low doses of chemotherapeutic drugs led to synergistic anti-tumor effects against AML cells. In an immunodeficient mouse model of human leukemia, Gnetin-C attenuated the formation of leukemia, depleted leukemia cells and improved survival. These findings suggest that Gnetin-C has antitumor activities in AML and supports the therapeutic potential of blocking two different pathways in AML.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzofurans; Cell Cycle; Dose-Response Relationship, Drug; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; HL-60 Cells; Humans; Karyotype; Leukemia, Myeloid, Acute; Mice, Inbred NOD; Mice, Knockout; Primary Cell Culture; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes; Time Factors; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; U937 Cells; Xenograft Model Antitumor Assays

Exploration of a new differentiation therapy that extends the range of differentiation for treating acute myeloid leukemia (AML) is attractive to researchers and clinicians. Here we report that diptoindonesin G (Dip G), a natural resveratrol aneuploid, exerts antiproliferative activity by inducing G2/M phase arrest and cell differentiation in AML cell lines and primary AML cells. Gene-profiling experiments showed that treating human leukemia HL-60 cells with Dip G was associated with a remarkable upregulation of STAT1 target gene expression, including IFIT3 and CXCL10. Mechanistically, Dip G activated ERK, which caused phosphorylation of STAT1 at Ser727 and selectively enhanced the interaction of p-STAT1 (Ser727) and p-ERK, further promoting their nuclear translocation. The nuclear translocation of p-STAT1 and p-ERK enhanced the transactivation of STAT1-targeted genes in AML cells. Furthermore, in vivo treatment of HL-60 xenografts demonstrated that Dip G significantly inhibited tumor growth and reduced tumor weight by inducing cell differentiation. Taken together, these results shed light on an essential role for ERK-mediated nuclear translocation of p-STAT1 (Ser727) and its full transcriptional activity in Dip G-induced differentiation of AML cells. Furthermore, these results demonstrate that Dip G could be used as a differentiation-inducing agent for AML therapy, particularly for non-acute promyelocytic leukemia therapy.

Topics: Animals; Antineoplastic Agents; Benzofurans; Caspase 3; Caspase Inhibitors; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Chemokine CXCL10; Extracellular Signal-Regulated MAP Kinases; HL-60 Cells; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Phosphorylation; STAT1 Transcription Factor; Up-Regulation

Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Benzophenones; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; K562 Cells; Leukemia, Myeloid, Acute; Molecular Structure; Phosphorylation; STAT5 Transcription Factor; Structure-Activity Relationship; Tumor Cells, Cultured

Mnk kinases regulate the phosphorylation and activation of the eukaryotic initiation factor 4E (eIF4E), a protein that plays key roles in the initiation of messenger RNA translation and whose activity is critical for various cellular functions. eIF4E is deregulated in acute myeloid leukemia (AML), and its aberrant activity contributes to leukemogenesis. We determined whether cercosporamide, an antifungal agent that was recently shown to act as a unique Mnk inhibitor, exhibits antileukemic properties. Treatment of AML cells with cercosporamide resulted in a dose-dependent suppression of eIF4E phosphorylation. Such suppression of Mnk kinase activity and eIF4E phosphorylation by cercosporamide resulted in dose-dependent suppressive effects on primitive leukemic progenitors (CFU-L) from AML patients and enhanced the antileukemic properties of cytarabine (Ara-C) or mammalian target of rapamycin (mTOR) complex 1 inhibition. Similarly, the combination of cercosporamide with cytarabine resulted in enhanced antileukemic responses in a xenograft mouse model in vivo. Altogether, this work demonstrates that the unique Mnk inhibitor cercosporamide suppresses phosphorylation of eIF4E and exhibits antileukemic effects, in support of future clinical-translational efforts involving combinations of Mnk inhibitors with cytarabine and/or mTOR inhibitors for the treatment of AML.

Topics: Adenosine Triphosphatases; Animals; Antineoplastic Agents; Benzofurans; Cation Transport Proteins; Cell Line, Tumor; Cell Proliferation; Copper-Transporting ATPases; Down-Regulation; Humans; K562 Cells; Leukemia, Myeloid, Acute; Mice; Neoplastic Stem Cells; Protein Kinase Inhibitors; U937 Cells; Xenograft Model Antitumor Assays

The leaves of Artocarpus tonkinensis are used in Vietnamese traditional medicine for treatment of arthritis, and the compound maesopsin 4-O-β-D-glucoside (TAT-2), isolated from them, inhibits the proliferation of activated T cells. Our goal was to test the anti-proliferative activity of TAT-2 on the T-cell leukemia, Jurkat, and on the acute myeloid leukemia, OCI-AML. TAT-2 inhibited the growth of OCI-AML (and additional acute myeloid leukemia cells) but not Jurkat cells. Growth inhibition was shown to be due to inhibition of proliferation rather than increase in cell death. Analysis of cytokine release showed that TAT-2 stimulated the release of TGF-β, yet TGF-β neutralization did not reverse the maesopsin-dependent effect. Gene expression profiling determined that maesopsin modulated 19 identifiable genes. Transcription factor CP2 was the gene most significantly modulated. Real-time PCR validated that up-regulation of sulphiredoxin 1 homolog (SRXN1), hemeoxygenase 1 (HMOX1), and breast carcinoma amplified sequence 3 (BCAS3) were consistently modulated.

Topics: Artocarpus; Benzofurans; Cell Death; Cell Growth Processes; Cell Line, Tumor; DNA-Binding Proteins; Dose-Response Relationship, Drug; Gene Expression; Gene Expression Profiling; Glucosides; Heme Oxygenase-1; HL-60 Cells; Humans; Jurkat Cells; Leukemia, Myeloid, Acute; Leukemia, T-Cell; Male; Middle Aged; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Oxidoreductases Acting on Sulfur Group Donors; T-Lymphocytes; Transcription Factors; Transforming Growth Factor beta; U937 Cells; Up-Regulation

The receptor tyrosine kinase FLT3 is constitutively activated by an internal tandem duplication (ITD) mutation within the juxtamembrane domain in 20-30% of patients with acute myeloid leukemia. In this study, we identified GTP-14564 as a specific kinase inhibitor for ITD-FLT3 and investigated the molecular basis of its specificity. GTP-14564 inhibited the growth of interleukin-3-independent Ba/F3 expressing ITD-FLT3 at 1 microM, whereas a 30-fold higher concentration of GTP-14564 was required to inhibit FLT3 ligand-dependent growth of Ba/F3 expressing wild type FLT3 (wt-FLT3). However, this inhibitor suppressed the kinase activities of wt-FLT3 and ITD-FLT3 equally, suggesting that the signaling pathways for proliferation differ between wt-FLT3 and ITD-FLT3. Analysis of downstream targets of FLT3 using GTP-14564 revealed STAT5 activation to be essential for growth signaling of ITD-FLT3. In contrast, wt-FLT3 appeared to mainly use the MAPK pathway rather than the STAT5 pathway to transmit a proliferative signal. Further analysis demonstrated that the first two tyrosines in an ITD were critical for STAT5 activation and growth induction but that all of the tyrosines in the juxtamembrane region were dispensable in terms of the proliferation signals of wt-FLT3. These results indicate that an ITD mutation in FLT3 elicits an aberrant STAT5 activation that results in increased sensitivity to GTP-14564. Thus, FLT3-targeted inhibition is an attractive approach, with the potential for selective cytotoxicity, to the treatment of ITD-FLT3-positive acute myeloid leukemia.

Topics: Animals; Benzofurans; Blotting, Western; Cell Division; Cell Line; DNA-Binding Proteins; DNA, Complementary; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Genes, Dominant; Genetic Vectors; Green Fluorescent Proteins; Humans; Inhibitory Concentration 50; Interleukin-3; Leukemia, Myeloid, Acute; Luminescent Proteins; MAP Kinase Signaling System; Mice; Milk Proteins; Models, Biological; Models, Chemical; Mutation; Phosphorylation; Precipitin Tests; Protein Structure, Tertiary; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Recombinant Proteins; Retroviridae; Signal Transduction; STAT5 Transcription Factor; Time Factors; Trans-Activators; Transfection; Tumor Cells, Cultured; Tyrosine

Topics: Acetates; Acute Disease; Anilides; Animals; Benzofurans; Bone Marrow; Bone Marrow Cells; Chlorine; Esterases; Guinea Pigs; Histocytochemistry; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Leukocytes; Methods; Mice; Rabbits; Rats