Acriflavine (ACF) is an antiseptic with anticancer properties, blocking the growth of solid and haematopoietic tumour cells. Moreover, this compound has been also shown to overcome the resistance of ...cancer cells to chemotherapeutic agents. ACF has been shown to target hypoxia‐inducible factors (HIFs) activity, which are key effectors of hypoxia‐mediated chemoresistance. In this study, we showed that ACF inhibits the growth and survival of chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cell lines in normoxic conditions. We further demonstrated that ACF down‐regulates STAT5 expression in CML and AML cells but activates STAT3 in CML cells in a HIF‐independent manner. In addition, we demonstrated that ACF suppresses the resistance of CML cells to tyrosine kinase inhibitors, such as imatinib. Our data suggest that the dual effect of ACF might be exploited to eradicate de novo or acquired resistance of myeloid leukaemia cells to chemotherapy.
Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are two closely related STAT family members that are crucial downstream effectors of tyrosine kinase oncoproteins such ...as FLT3‐ITD in acute myeloid leukemia (AML) and BCR‐ABL in chronic myeloid leukemia (CML). We recently developed and reported the synthesis of a first molecule called 17 f that selectively inhibits STAT5 signaling in myeloid leukemia cells and overcomes their resistance to chemotherapeutic agents. To improve the antileukemic effect of 17 f, we synthesized ten analogs of this molecule and analyzed their impact on cell growth, survival, chemoresistance and STAT5 signaling. Two compounds, 7 a and 7 a’, were identified as having similar or higher antileukemic effects in various AML and CML cell lines. Both molecules were found to be more effective than 17 f at inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML.
Lead on: To improve the antileukemic activity of lead compound, 17 f, new derivatives were synthesized by pharmacomodulation. Two compounds, 7 a and 7 a’, showed similar or higher antileukemic effects in various acute and chronic myeloid leukemias cell lines. Both compounds were found to be more effective than 17 f in inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML cells.
Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment ...approaches, new specific molecules are needed. The G‐quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine‐rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9‐bis(substituted‐aminomethyl)phenyl‐1,10‐phenanthroline derivatives (1a–i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4‐11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c‐MYC, BCL‐2, and K‐RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g–i were tested for telomerase activity in HuT78 and MV4‐11 protein extracts.
2,9‐Bis(substituted‐aminomethyl)phenyl‐1,10‐phenanthrolines 1a–i were designed, synthesized, and evaluated against five human myeloid leukemia cell lines. Their ability to stabilize the c‐MYC, BCL‐2, and K‐RAS oncogene promoter G4 structures was determined by fluorescence resonance energy transfer melting assay and native mass spectrometry. Telomerase activity in HuT78 and MV4‐11 protein extracts was investigated in the presence of the more bioactive ligands.
Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic ...cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.
Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) ...and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure-activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (
and
) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.
Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation ...and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo
,
furan derivatives derived from cercosporamide. Among them, lead compound
was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC
value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and
larvae testing for acute toxicity.
We identified a new series of quinoxaline-2-carboxylic acid derivatives, targeting the human proviral integration site for Moloney murine leukemia virus-1 (HsPim-1) kinase. Seventeen analogues were ...synthesized providing useful insight into structure-activity relationships studied. Docking studies realized in the ATP pocket of HsPim-1 are consistent with an unclassical binding mode of these inhibitors. The lead compound 1 was able to block HsPim-1 enzymatic activity at nanomolar concentrations (IC50 of 74 nM), with a good selectivity profile against a panel of mammalian protein kinases. In vitro studies on the human chronic myeloid leukemia cell line KU812 showed an antitumor activity at micromolar concentrations. As a result, compound 1 represents a promising lead for the design of novel anticancer targeted therapies.
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Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of ...leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias.
During World War I (WWI), infectious diseases including tetanus were among the most important causes of death. Even though its efficacy was somewhat controversial before the war, tetanus antiserum ...played a key role in reducing the mortality of this disease. A vial of tetanus antiserum dating back from WWI, left behind on the French battlefield by the US Army, was borrowed from a private collection and opened. The serum contained within was characterized by orthogonal biochemical techniques to determine if any neutralizing IgGs could remain after 100 years of storage. In vitro analysis by Size Exclusion Chromatography and Serum Protein Electrophoresis suggested the presence of residual IgG. In spite of our hopes, these IgGs were not able to protect mice against tetanus toxin challenge in a neutralizing assay. Even though our results indicate the presence of remaining IgGs inside the serum, they were functionally disabled. These results show that obscurity alone is insufficient to protect IgGs from degradation over very long periods of time at room temperature.HighlightsTetanus antiserum found its place in the therapeutic arsenal during World War IA century-old vial of tetanus antiserum was opened for biochemical and in vivo characterizationBiochemical assays revealed the presence of proteins having all the characteristics of IgGsThe serum was unable to protect mice against toxinic challenge
During World War I (WWI), infectious diseases including tetanus were among the most important causes of death. Even though its efficacy was somewhat controversial before the war, tetanus antiserum ...played a key role in reducing the mortality of this disease. A vial of tetanus antiserum dating back from WWI, left behind on the French battlefield by the US Army, was borrowed from a private collection and opened. The serum contained within was characterized by orthogonal biochemical techniques to determine if any neutralizing IgGs could remain after 100 years of storage. In vitro analysis by Size Exclusion Chromatography and Serum Protein Electrophoresis suggested the presence of residual IgG. In spite of our hopes, these IgGs were not able to protect mice against tetanus toxin challenge in a neutralizing assay. Even though our results indicate the presence of remaining IgGs inside the serum, they were functionally disabled. These results show that obscurity alone is insufficient to protect IgGs from degradation over very long periods of time at room temperature.
Highlights
Tetanus antiserum found its place in the therapeutic arsenal during World War I
A century-old vial of tetanus antiserum was opened for biochemical and in vivo characterization
Biochemical assays revealed the presence of proteins having all the characteristics of IgGs
The serum was unable to protect mice against toxinic challenge
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