Growth inhibitory activity of Ankaferd hemostat on primary melanoma cells and cell lines

Despite much research in the last centuries, treatment of malignant melanoma is still challenging because of its mostly unnoticeable metastatic spreading and aggressive growth rate. Therefore, the discovery of novel drug leads is an important goal. In a previous study, we have isolated several shikonin derivatives from the roots of Onosma paniculata Bureau & Franchet (Boraginaceae) which evolved as promising anticancer candidates. β,β-Dimethylacrylshikonin (1) was the most cytotoxic derivative and exhibited strong tumor growth inhibitory activity, in particular, towards melanoma cells. In this study, we synthesized eighteen novel shikonin derivatives in order to obtain compounds which exhibit a higher cytotoxicity than 1. We investigated their cytotoxic potential against various melanoma cell lines and juvenile skin fibroblasts. The most active compound was (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopropylacetate (cyclopropylacetylshikonin) (6). It revealed significant stronger tumor growth inhibitory activity towards two melanoma cell lines derived from metastatic lesions (WM164 and MUG-Mel2). Further investigations have shown that 6 induced apoptosis caspase-dependently, increased the protein levels of cleaved PARP, and led to double-stranded DNA breaks as shown by phosphorylation of H2AX. Cell membrane damage and cell cycle arrest were not observed.

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Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

Pharmaceuticals ◽

10.3390/ph14010049 ◽

2021 ◽

Vol 14 (1) ◽

pp. 49

Author(s):

David Méndez-Luna ◽

Loreley Araceli Morelos-Garnica ◽

Juan Benjamín García-Vázquez ◽

Martiniano Bello ◽

Itzia Irene Padilla-Martínez ◽

...

Keyword(s):

Binding Site ◽

Cell Lines ◽

Cancer Cell ◽

Inhibitory Activity ◽

In Silico ◽

Cancer Cell Lines ◽

Pancreatic Cancer Cells ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

New Compounds

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

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Synthesis of quaternary 8-(1-acylethene-1-yl)-13-methylcoptisine chlorides and their selective growth inhibitory activity between human cancer cell lines and normal intestinal epithelial cell-6

Chinese Chemical Letters ◽

10.1016/j.cclet.2017.08.026 ◽

2018 ◽

Vol 29 (1) ◽

pp. 131-135 ◽

Cited By ~ 1

Author(s):

Zhi-Hui Zhang ◽

Yu Yan ◽

An-Jun Deng ◽

Hai-Jing Zhang ◽

Zhi-Hong Li ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Lines ◽

Inhibitory Activity ◽

Intestinal Epithelial Cell ◽

Human Cancer ◽

Intestinal Epithelial ◽

Human Cancer Cell ◽

Human Cancer Cell Lines ◽

Growth Inhibitory ◽

Growth Inhibitory Activity

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MODELING and Targeting ERG-INDUCED Acute MYELOID LEUKEMIA (AML).

Blood ◽

10.1182/blood.v114.22.475.475 ◽

2009 ◽

Vol 114 (22) ◽

pp. 475-475

Author(s):

Gil Smooha ◽

Yehudit Birger ◽

Liat Goldberg ◽

Jasmine Jacob-Hirsch ◽

Ninette Amariglio ◽

...

Keyword(s):

Cell Lines ◽

Inhibitory Activity ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Cellular Systems ◽

Gene Set Enrichment Analysis ◽

Chromosome 21 ◽

Ras Signaling ◽

Growth Inhibitory ◽

Growth Inhibitory Activity

Abstract Abstract 475 ERG is an oncogene located on the long arm of human chromosome 21 that encodes an ETS transcription factor that has been reported to be involved in normal and aberrant megakaryopoiesis (Salek-Ardakani et al Cancer Res. 2009;69:4665; Stankiewicz et al Blood 2009;113:3337). High ERG expression has also been reported associated with poor prognosis of cytogenetically normal AML (Marcucci et al J Clin Oncol. 2007;25:3337). Thus, deciphering the molecular targets and oncogenic pathways activated by overexpressed ERG protein is likely to lead to more effective therapy for ERG-related myeloid leukemias. Towards these goals we have combined in-vitro and in-vivo approaches. We have created transgenic mice expressing the ERG3 hematopoietic isoform under the VAV promoter. All these mice die from invasive acute megakaryocytic or undifferentiated myeloid leukemia by the age of 5 months. The leukemias are transplantable, and primary growth factor dependent leukemic cell lines, suitable for pharmacological and molecular studies, have been established. To identify ERG target genes and proteins, we have analyzed gene expression in two “mirror-image” cellular systems – shRNA mediated knockdown of ERG in Meg01 megakaryocytic leukemia cells and overexpression of ERG in K562 erythroleukemia cells. Gene Set Enrichment Analysis (GSEA) demonstrated that the “ERG gene-associated expression signature” in these cell lines is enriched with genes that were also identified in primary human AML characterized by ERG overexpression. By chromatin immunoprecipitation, we then identified specific, direct ERG targets and confirmed their expression in samples from ERG transgenic leukemias and primary human “ERG-overexpressing” AMLs. Surprisingly, we observed that the lymphoid kinase Bruton agammaglobulinemia tyrosine kinase (BTK) is an ERG direct target that is upregulated in both ERG overexpressing mouse and human leukemias. Preliminary experiments have demonstrated activity of a BTK inhibitor on ERG transgenic and ERG overexpressing human AML cells. ERG overexpression also induced marked activation of RAS signaling as supported by elevated levels of RAS-GTP and its downstream targets and significant growth inhibitory activity caused by a novel RAS inhibitor, farnesylthiosalicylic acid (Salirasib), that disrupts the spatiotemporal localization of active Ras (Rotblat et al Methods Enzymol. 2008;439:467) was observed. Dramatic growth inhibitory activity has also been induced by two novel compounds that induce megakaryocytic polyploidization, suggesting a potential role for “differentiation” therapy of ERG-related leukemias. Thus we have created a mouse model for ERG-related AML and characterized several genes and biochemical pathways that are susceptible to pharmacological inhibition. Our studies are not only likely to decipher the mechanisms by which ERG overexpression contributes to leukemogenesis, but also provide a platform for preclinical studies of novel therapeutics of these poor prognosis leukemias. Disclosures: No relevant conflicts of interest to declare.

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