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Antiproliferative and proapoptotic effects of a pyrrole containing arylthioindole in human Jurkat leukemia cell line and multidrug-resistant Jurkat/A4 cells.

ABSTRACT: Recently, a series of novel arylthioindole compounds, potent inhibitors of tubulin polymerization and cancer cell growth, were synthesized. In the present study the effects of 2-(1H-pyrrol-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (ATI5 compound) on cell proliferation, cell cycle progression, and induction of apoptosis in human T-cell acute leukemia Jurkat cells and their multidrug resistant Jurkat/A4 subline were investigated. Treatment of the Jurkat cells with the ATI5 compound for 48 hrs resulted in a strong G2/M cell cycle arrest and p53-independent apoptotic cell death accompanied by the induction of the active form of caspase-3 and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage. ATI5 treatment also caused non-cell death related mitotic arrest in multidrug resistant Jurkat/A4 cells after 48 hrs of treatment suggesting promising opportunities for the further design of pyrrole-containing ATI compounds as anticancer agents. Cell death resistance of Jurkat/A4 cells to ATI5 compound was associated with alterations in the expression of pro-survival and anti-apoptotic protein-coding and microRNA genes. More importantly, findings showing that ATI5 treatment induced p53-independent apoptosis are of great importance from a therapeutic point of view since p53 mutations are common genetic alterations in human neoplasms.

SUBMITTER: Philchenkov AA

PROVIDER: S-EPMC4847820 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Antiproliferative and proapoptotic effects of a pyrrole containing arylthioindole in human Jurkat leukemia cell line and multidrug-resistant Jurkat/A4 cells.

Philchenkov Alex A AA Zavelevich Michael P MP Tryndyak Volodymyr P VP Kuiava Ludmila M LM Blokhin Dmitry Yu DY Miura Koh K Silvestri Romano R Pogribny Igor P IP

Cancer biology & therapy 20150101 12

Recently, a series of novel arylthioindole compounds, potent inhibitors of tubulin polymerization and cancer cell growth, were synthesized. In the present study the effects of 2-(1H-pyrrol-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (ATI5 compound) on cell proliferation, cell cycle progression, and induction of apoptosis in human T-cell acute leukemia Jurkat cells and their multidrug resistant Jurkat/A4 subline were investigated. Treatment of the Jurkat cells with the ATI5 compound for 48 h ...[more]

PMID: 26785947

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Project description:BackgroundMarine sponge is a rich natural resource of many pharmacologically important compounds.ObjectiveMarine sponge Hyrtios erectus, collected from North Bay, South Andaman Sea, India, was screened for potential antiproliferative and proapoptotic properties on a breast adenocarcinoma cell line (MCF-7).Materials and methods3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to test the antiproliferative and cytotoxicity effects of the sponge extract. Analysis of apoptosis and cell cycle stages were done by flow cytometry. The expression of several apoptotic-related proteins in MCF-7 cells treated by the extract was evaluated by Western blot analysis. Various analytical techniques including Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry, and nuclear magnetic resonance were employed to determine the identity of the active compounds in the sponge extract.ResultsN-Hexane extract of the sponge inhibited proliferation of the MCF-7 cell line in a dose- and time-dependent manner. Exposure of the sponge extract triggered apoptosis of the MCF-7 cells, induced DNA fragmentation, and arrested the cells in G2/M phase. Treatment of the sponge extract induced downregulation of antiapoptotic Bcl-2 protein and upregulation of Bax, caspase-3, caspase-9, and fragmented poly(ADP ribose)polymerase proteins in MCF-7 cells. Five bioactive compounds have been identified in the extract.ConclusionThe antiproliferative and proapoptotic activities of the tested extract suggested the pharmacologic potential of the identified compounds. Further characterization of the identified compounds are in progress.SummaryThe N-hexane extract of the marine sponge Hyrtios erectus, collected from North Bay, South Andaman Sea, India, showed potential antiproliferative and proapoptotic properties against a breast adenocarcinoma cell line (MCF-7).The sponge extract retarded the growth of breast carcinoma cell line MCF-7 cells in a time- and dose-dependent manner.The sponge extract induced apoptosis of breast cancer cell line MCF-7 and arrested cells in G2/M phase.The sponge extract induced downregulation of Bcl-2 protein in MCF-7 cell line and upregulation of Bax, caspase-3, and cleaved PARP. Five bioactive compounds have been identified in the extract. Abbreviations used: GC-MS: Gas chromatography-mass spectrometry; FT-IR: Fourier transform infrared spectroscopy; NMR: Nuclear magnetic resonance; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

Project description:Multidrug resistance, a major problem that leads to failure of anticancer chemotherapy, requires the development of new drugs. Repurposing of established drugs is a promising approach for overcoming this problem. An example of such drugs is niclosamide, a known anthelmintic that is now known to be cytotoxic and cytostatic against cancer cells. In this study, niclosamide showed varying activity against different cancer cell lines. It revealed better activity against hematological cancer cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines MDA-MB-231, A549, and HT-29. The multidrug resistant CEM/ADR5000 cells were similar sensitive as their sensitive counterpart CCRF-CEM (resistance ration: 1.24). Furthermore, niclosamide caused elevations in reactive oxygen species and glutathione (GSH) levels in leukemia cells. GSH synthetase (GS) was predicted as a target of niclosamide. Molecular docking showed that niclosamide probably binds to the ATP-binding site of GS with a binding energy of -9.40 kcal/mol. Using microscale thermophoresis, the binding affinity between niclosamide and recombinant human GS was measured (binding constant: 5.64 μM). COMPARE analyses of the NCI microarray database for 60 cell lines showed that several genes, including those involved in lipid metabolism, correlated with cellular responsiveness to niclosamide. Hierarchical cluster analysis showed five major branches with significant differences between sensitive and resistant cell lines (p = 8.66 × 105). Niclosamide significantly decreased nuclear factor of activated T-cells (NFAT) activity as predicted by promoter binding motif analysis. In conclusion, niclosamide was more active against hematological malignancies compared to solid tumors. The drug was particularly active against the multidrug-resistant CEM/ADR5000 leukemia cells. Inhibition of GSH synthesis and NFAT signaling were identified as relevant mechanisms for the anticancer activity of niclosamide. Gene expression profiling predicted the sensitivity or resistance of cancer cells to niclosamide.

Dataset Information

Antiproliferative and proapoptotic effects of a pyrrole containing arylthioindole in human Jurkat leukemia cell line and multidrug-resistant Jurkat/A4 cells.

Publications

Antiproliferative and proapoptotic effects of a pyrrole containing arylthioindole in human Jurkat leukemia cell line and multidrug-resistant Jurkat/A4 cells.

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