Concentration and sequence dependent synergism of ethyldeshydroxy-sparsomycin in combination with antitumor agents

Hofs, H. P.; Wagener, D.J.T.; Valk-Bakker, V. de; Rennes, Helga van; Ottenheijm, H.C.J.; Grip, W.J. de

doi:10.1097/00001813-199402000-00006

Cited by 4 publications

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“…CHX has been reported to enhance the cytotoxicity of the anthracycline, epirubicin, against P388 murine leukemic cells [42] and to potentiate Dxr toxicity in RKO-E6 cells [43]. Sparsomycin, pretazettine, and HHT also show synergy with antitumor agents against tumor cells ex vivo [44], [45], [46], [47]. Finally, translation elongation inhibitors have been shown to sensitize PC3 cells to TRAIL-induced apoptosis [48] and A549 lung cancer or K562 leukemia cells to cisplatin [49].…”

Section: Discussionmentioning

confidence: 99%

Altering Chemosensitivity by Modulating Translation Elongation

et al. 2009

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BackgroundThe process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Eμ-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents.Methodology/Principal FindingsHere, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Eμ-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor.Conclusion/SignificanceOur results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations.

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Section: Discussionmentioning

confidence: 99%

Altering Chemosensitivity by Modulating Translation Elongation

et al. 2009

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“…Nevertheless, the synthesis of a series of sparsomycin derivatives with higher inhibitory activities (30) has led to a reappraisal of its potential as an anticancer drug (5,7).…”

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Characterization of Sparsomycin Resistance in Streptomyces sparsogenes

Lázaro

Sanz

Remacha

et al. 2002

Antimicrob Agents Chemother

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The antitumor antibiotic sparsomycin, produced by Streptomyces sparsogenes, is a universal translation inhibitor that blocks the peptide bond formation in ribosomes from all species. Sparsomycin-resistant strains were selected by transforming the sensitive Streptomyces lividans with an S. sparsogenes library. Resistance was linked to the presence of a plasmid containing an S. sparsogenes 5.9-kbp DNA insert. A restriction analysis of the insert traced down the resistance to a 3.6-kbp DNA fragment, which was sequenced. The analysis of the fragment nucleotide sequence together with the previous restriction data associate the resistance to srd, an open reading frame of 1,800 nucleotides. Ribosomes from S. sparsogenes and the S. lividans-resistant strains are equally sensitive to the inhibitor and bind the drug with similar affinity. Moreover, the drug was not modified by the resistant strains. However, resistant cells accumulated less antibiotic than the sensitive ones. In addition, membrane fractions from the resistant strains showed a higher capacity for binding the drug. The results indicate that resistance in the producer strain is not connected to either ribosome modification or drug inactivation, but it might be related to an alteration in the sparsomycin permeability barrier.

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Biochemical studies on the production of Sparsomycin antibiotic by Pseudomonas aeurginosa, AZ-SH-B8 using plastic wastes as fermented substrate

Atta

Radwan

2012

Journal of Saudi Chemical Society

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Concentration and sequence dependent synergism of ethyldeshydroxy-sparsomycin in combination with antitumor agents

Cited by 4 publications

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Altering Chemosensitivity by Modulating Translation Elongation

Altering Chemosensitivity by Modulating Translation Elongation

Characterization of Sparsomycin Resistance in Streptomyces sparsogenes

Biochemical studies on the production of Sparsomycin antibiotic by Pseudomonas aeurginosa, AZ-SH-B8 using plastic wastes as fermented substrate

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