The Biological Activity of the Novel Vinca Alkaloids 4-chlorochablastine and 4-chlorochacristine

2019 ◽  
Vol 19 (3) ◽  
pp. 222-230 ◽  
Author(s):  
Gracia Montag ◽  
Helga Stopper ◽  
Quoc Anh Ngo ◽  
Henning Hintzsche
Keyword(s):  
Biological Activity ◽  
Cellular Proliferation ◽  
Leukemia Cell ◽  
Similar Efficacy ◽  
Leukemia Cell Line ◽  
Vinca Alkaloids ◽  
Late Apoptosis ◽  
G1 Cells ◽  
New Compounds ◽  
Effective Drugs

Background: Vinca alkaloids are important cancer drugs belonging to the class of antimitotic agents. The most commonly used substances are vinblastine and vincristine, other compounds are vinorelbine and vinflunine. All of them are very effective drugs but their use is limited by severe side-effects including neurotoxicity and bone marrow depression. Therefore, it is very important to develop novel vinca alkaloids with similar efficacy but lower toxicity. </P><P> Methods: Here, we analyzed two new compounds, 4-chlorochablastine and 4-chlorochacristine, with regard to their biological activity. These novel compounds were applied to a leukemia cell line at clinically relevant concentrations. For comparison, the established vinca alkaloids vinblastine, vincristine, vinorelbine, and vinflunine were also tested. </P><P> Results: Both novel substances decreased cellular proliferation. Apoptosis was found to be increased using two different methods reflecting early and late apoptosis. Cell cycle analysis revealed a clear decrease in G1-cells and an increase in G2/M-cells indicating an arrest in mitosis. In general, 4- chlorochablastine and 4-chlorochacristine caused these effects at concentrations higher than those needed for vinblastine, vincristine, and vinorelbine, but the potency was approximately in the range of vinflunine. </P><P> Conclusion: Taken together, the results show first indications that these novel vinca alkaloids might be effective and that they warrant further analysis.

Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 925-932 ◽  
Author(s):  
Michael C. Heinrich ◽  
Diana J. Griffith ◽  
Brian J. Druker ◽  
Cecily L. Wait ◽  
Kristen A. Ott ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Tyrosine Kinase Activity ◽  
Sti 571

Abstract STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.

scholarly journals A New Guaiane-type Sesquiterpenoid from a Bornean Soft Coral, Xenia stellifera

2018 ◽  
Vol 13 (1) ◽  
pp. 1934578X1801300 ◽  
Author(s):  
Chin-Soon Phan ◽  
Takashi Kamada ◽  
Takahiro Ishii ◽  
Toshiyuki Hamada ◽  
Charles Santhanaraju Vairappan
Keyword(s):  
Biological Activity ◽  
T Cell ◽  
Cell Line ◽  
Spectroscopic Data ◽  
Soft Coral ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

A new guaiane-type sesquiterpenoid, 10β- O-methyl-1αH,5αH-guaia-6-en-4β-ol (1) along with two known compounds, 10- O -methyl alismoxide (2) and alismoxide (3) were isolated from a population of Bornean soft coral Xenia stellifera. The structure of this metabolite was elucidated based on spectroscopic data such as NMR and HRESIMS. These compounds were evaluated for their biological activity against adult T-cell leukemia cell line.

Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 925-932 ◽  
Author(s):  
Michael C. Heinrich ◽  
Diana J. Griffith ◽  
Brian J. Druker ◽  
Cecily L. Wait ◽  
Kristen A. Ott ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Map Kinase ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Tyrosine Kinase Activity ◽  
Sti 571

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.

Synthesis, anticancer activity, SAR and binding mode of interaction studies of substituted pentanoic acids: part II

2021 ◽  
Author(s):  
Sanchita Datta ◽  
Amit Kumar Halder ◽  
Nilanjan Adhikari ◽  
Sk Abdul Amin ◽  
Sanjib Das ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Leukemia Cell ◽  
Binding Mode ◽  
Docking Studies ◽  
Leukemia Cell Line ◽  
Pentanoic Acid ◽  
Dna Deformation ◽  
Pharmacokinetic Properties ◽  
New Compounds ◽  
Inhibiting Property

Aim: Our previous results suggest that phenyl/naphthylacetyl pentanoic acid derivatives may exhibit dual MMP-2 and HDAC8 inhibitory activities and show effective cytotoxic properties. Methodology: Here, 13 new compounds (C1–C13) were synthesized and characterized. Along with these new compounds, 16 previously reported phenyl/napthylacetyl pentanoic acid derivatives (C14–C29) were biologically evaluated. Results: Compounds C6 and C27 showed good cytotoxicity against leukemia cell line Jurkat E6.1. The mechanisms of cytotoxicity of these compounds were confirmed by DNA deformation assay and reactive oxygen species assay. MMP-2 and HDAC8 expression assays suggested the dual inhibiting property of these two compounds. These findings were supported by results of molecular docking studies. In silico pharmacokinetic properties showed compounds C6 and C27 have high gastrointestinal absorption. Conclusion: This study highlights the action of phenyl/naphthylacetyl pentanoic acid derivatives as anticancer agents.

scholarly journals Characterising the Biological Activity of a Trichlorovinyl Cysteine-Containing Mycothiol Analogue

2021 ◽  
Author(s):  
◽  
Phoebe Harmos
Keyword(s):  
Biological Activity ◽  
Mode Of Action ◽  
Leukemia Cell ◽  
Negative Control ◽  
Leukemia Cell Line ◽  
Immunomodulatory Activity ◽  
Lead Compound ◽  
Significant Toxicity ◽  
Cellular Target ◽  
Cancer Agent

<p>Cancer is a disease characterised by the uncontrolled growth of mutated cells, and is one of the leading causes of death worldwide, with over a third of people diagnosed with cancer in their lifetime. Despite extensive investment of both time and money in cancer research, poor patient outcomes and quality of life, and the evolution of treatment resistant cancers indicates that continued research, and more efficacious therapies are required. A recent investigation identified a mycothiol analogue which displayed significant toxicity in the promyelocytic leukemia cell line (HL60). Designed as a negative control, no biological activity was expected from this compound and its cellular target and mode of action are unknown.  This thesis describes the synthesis of a toxic trichlorovinyl cysteine-containing analogue of mycothiol, and the attempted synthesis of a propynylated and fluorescent derivative of this. The research also details immunomodulatory investigations, which were undertaken to probe the mode of action of the lead compound, and to determine whether its precursor, N-Boc-S-trichlorovinyl cysteine, induced toxicity through the same mechanism. The lead compound demonstrated mild immunomodulatory activity in splenocytes isolated from euthanised C57BL/6 mice, and enzyme linked immunosorbent assays revealed a likely Th2 mediated response, induced by the production of IL-4. The precursor however appears to promote a strong pro-inflammatory response, by inducing IL-17a production, which is widely considered a deleterious immune response in cancer. Whilst further work is required to determine the cellular target of the lead compound, the research described demonstrates the potential for this compound as an anti-cancer agent, while the precursor appears inappropriate for further development.</p>

A Novel Function of Stat1α and Stat3 Proteins in Erythropoietin-Induced Erythroid Differentiation of a Human Leukemia Cell Line

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 462-471 ◽  
Author(s):  
Keita Kirito ◽  
Mie Uchida ◽  
Masaaki Takatoku ◽  
Koichi Nakajima ◽  
Toshio Hirano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Leukemia Cell ◽  
Erythroid Differentiation ◽  
Dominant Negative ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
A Cell ◽  
Macrophage Colony

We recently determined that erythropoietin (EPO) activates 3 members of the signal transducer and activator of transcription (STAT) family, Stat1α, Stat3, and Stat5, in the human EPO-dependent cell lines, UT-7 and UT-7/EPO (Kirito et al, J Biol Chem 272:16507, 1997). In addition, we have shown that Stat1α, but not Stat3, is involved in EPO-induced cellular proliferation. In this study, we examined the roles of Stat1α and Stat3 in EPO-induced erythroid differentiation. UT-7/GM was used as a model system, because this cell line can differentiate into erythroid-lineage cells with EPO treatment (Komatsu et al, Blood 89:4021, 1997). We found that EPO did not activate Stat1α or Stat3 in UT-7/GM cells. Transfection experiments showed that both Stat1α and Stat3 inhibited the induction by EPO of γ-globin and erythroid-specific 5-aminolevulinate synthetase transcripts, resulting in a reduction of the percentage of hemoglobin-positive cells. Dominant negative forms of Stat1α or Stat3 promoted the EPO-induced erythroid differentiation of UT-7/GM cells, even in the presence of granulocyte-macrophage colony-stimulating factor, although this cytokine never induced erythroid differentiation of the parent UT-7/GM cells with or without EPO. A cell cycle analysis showed that the constitutive activation of Stat1α, but not Stat3, shortened the period of G0/G1 prolongation caused by EPO stimulation. Taken together, our data suggest that Stat1α and Stat3 act as negative regulators in EPO-induced erythroid differentiation. Specifically, Stat1α may activate a cell cycle-associated gene(s), leading to the entry of cells into the cell cycle.

A Novel Function of Stat1α and Stat3 Proteins in Erythropoietin-Induced Erythroid Differentiation of a Human Leukemia Cell Line

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 462-471 ◽  
Author(s):  
Keita Kirito ◽  
Mie Uchida ◽  
Masaaki Takatoku ◽  
Koichi Nakajima ◽  
Toshio Hirano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Leukemia Cell ◽  
Erythroid Differentiation ◽  
Dominant Negative ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
A Cell ◽  
Macrophage Colony

Abstract We recently determined that erythropoietin (EPO) activates 3 members of the signal transducer and activator of transcription (STAT) family, Stat1α, Stat3, and Stat5, in the human EPO-dependent cell lines, UT-7 and UT-7/EPO (Kirito et al, J Biol Chem 272:16507, 1997). In addition, we have shown that Stat1α, but not Stat3, is involved in EPO-induced cellular proliferation. In this study, we examined the roles of Stat1α and Stat3 in EPO-induced erythroid differentiation. UT-7/GM was used as a model system, because this cell line can differentiate into erythroid-lineage cells with EPO treatment (Komatsu et al, Blood 89:4021, 1997). We found that EPO did not activate Stat1α or Stat3 in UT-7/GM cells. Transfection experiments showed that both Stat1α and Stat3 inhibited the induction by EPO of γ-globin and erythroid-specific 5-aminolevulinate synthetase transcripts, resulting in a reduction of the percentage of hemoglobin-positive cells. Dominant negative forms of Stat1α or Stat3 promoted the EPO-induced erythroid differentiation of UT-7/GM cells, even in the presence of granulocyte-macrophage colony-stimulating factor, although this cytokine never induced erythroid differentiation of the parent UT-7/GM cells with or without EPO. A cell cycle analysis showed that the constitutive activation of Stat1α, but not Stat3, shortened the period of G0/G1 prolongation caused by EPO stimulation. Taken together, our data suggest that Stat1α and Stat3 act as negative regulators in EPO-induced erythroid differentiation. Specifically, Stat1α may activate a cell cycle-associated gene(s), leading to the entry of cells into the cell cycle.

Single Oral Administration of KRN383, a Novel Flt3 Inhibitor, Induces Eradication of the Xenograft Tumor Harboring Flt3 Mutation in Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2545-2545
Author(s):  
Uichi Nishiyama ◽  
Masako Ozai ◽  
Rieko Yoshioka ◽  
Tetsuya Yoshino ◽  
Yuko Ogasawara ◽  
...  
Keyword(s):  
Oral Administration ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Therapeutic Potential ◽  
Leukemia Cell ◽  
Tumor Xenograft ◽  
Leukemia Cell Line ◽  
Activating Mutations ◽  
Flt3 Inhibitor

Abstract Constitutively activating mutations of the Flt3 receptor tyrosine kinase including internal tandem duplication (ITD) mutations are the most common genetic abnormality and are associated with a poor prognosis in acute myeloid leukemia (AML) patients. Therefore, Flt3 is a potential therapeutic target in AML. We show here the results of pre-clinical studies on KRN383, a novel orally active quinoline-urea derivative. KRN383 inhibited autophosphorylation of ITD mutant (IC50=1.3nM) and wild type (IC50=0.4nM) Flt3 in the leukemia cell line MV4-11 and THP-1, respectively. KRN383 induced cell cycle arrest, apoptosis and suppression of proliferation (IC50=0.8nM) of MV4-11 in vitro. Single (80mg/kg) or consecutive (20mg/kg/d X 28d) oral administration of KRN383 induced eradication (longer than 6mo) of tumor xenograft (MV4-11) subcutaneously implanted in all nude mice. All these effects were superior to those of SU11248, a precedent Flt3 inhibitor. In addition, single (80mg/kg) administration of KRN383 prolonged the survival of SCID mice to which MOLM-13 (ITD mutant positive leukemia cell line) was intravenously transplanted. The advantage of KRN383 over SU11248 was more obvious in in vitro studies in which the inhibition of Flt3 autophosphorylation and cellular proliferation induced by transient exposure with those drugs was determined. These results indicate that KRN383 has therapeutic potential in ITD mutant positive AML. Furthermore, eradication induced by single administration of KRN383 suggests that KRN383 provides feasibility to set wide variety of clinical regimens including multi-cycle and combination therapies. In vitro activity of Ki23819, hydrochloride salt of KRN383, is also to be reported in this ASH meeting (Komeno et al.).

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