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Korystov, Yu. N.; Kublik, L. N.; Kudryavtsev, A. A.; Levitman, M. Kh.; Shaposhnikova, V. V.; Drinyaev, V. A.; Mosin, V A; Kruglyak, E. B.; Sterlina, T. S.; Chailakhyan, L. M.

doi:10.1023/a:1026164930069

Cited by 5 publications

(1 citation statement)

References 4 publications

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“…Administration of the mitochondrial H(+)-ATP synthase inhibitor, oligomycin, to in vitro cancer cell systems inhibited the oxygen consumption responsible for mitochondrial ATP generation (37), an effect restricted to cancer cells (38). The NSAID, oxaprozin, induces apoptosis of activated monocytes in a dose-dependent manner, associated with the inhibition of AKT and NF-κB phosphorylation, and the activation of caspase-3 (39).…”

Section: Discussionmentioning

confidence: 99%

Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer

Zerbini

Bhasin

Vasconcellos

et al. 2014

Molecular Cancer Therapeutics

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While early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. We previously established a highly accurate signature of differentially expressed genes that distinguish ccRCC from normal kidney. The purpose of the current study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anti-cancer therapy. Here we demonstrate that one of the drugs predicted to revert the RCC gene signature towards normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. ccRCC-specific gene expression signatures of individual patients were used to query the C-MAP software. Eight drugs with negative correlation and p-value <0.05 were analyzed for efficacy against RCC in vitro and in vivo. Our data demonstrate consistency across most ccRCC patients for the set of high scoring drugs. Most of the selected high scoring drugs potently induce apoptosis in RCC cells. Several drugs also demonstrate selectivity for VHL negative RCC cells. Most importantly, at least one of these drugs, pentamidine, slows tumor growth in the 786-O human ccRCC xenograft mouse model. Our findings suggest that pentamidine might be a new therapeutic agent to be combined with current standard-of-care regimens for metastatic ccRCC patients and support our notion that IBA combined with C-MAP analysis enables repurposing of FDA-approved drugs for potential anti-RCC therapy.

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Section: Discussionmentioning

confidence: 99%

Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer

Zerbini

Bhasin

Vasconcellos

et al. 2014

Molecular Cancer Therapeutics

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A new strain of Streptomyces avermitilis produces high yield of oligomycin A with potent anti-tumor activity on human cancer cell lines in vitro

Lin

Wen

et al. 2009

Appl Microbiol Biotechnol

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A new actinomycete strain, isolated from soil in China, strongly inhibited in vitro proliferation of human hepatoma, chronic myelogenous leukemia, and colonic carcinoma cell lines. The strain, designated L033, was identified as a strain of Streptomyces avermitilis based on cultural property, morphology, carbon source utilization, 16s rRNA gene analysis, and DNA-DNA relatedness studies. The anticancer component from L033 was purified to homogeneity by preparative positive-phase high-performance liquid chromatography and crystallization. Nuclear magnetic resonance and mass spectrometric analysis showed that this compound had the same structure as oligomycin A. Different with other reported naturally occurring strains of S. avermitilis, L033 produced high quantity of oligomycin A (maximal 1,461 microg/ml). Therefore, L033 was considered of great potential as an industrial oligomycin-A-producing strain.

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Enhancement and Selective Production of Oligomycin through Inactivation of Avermectin’s Starter Unit in Streptomyces avermitilis

2006

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Oligomycin and its analogues, produced by Streptomyces avermitilis and other actinomycetes, are of interest for their potent and selective biological activities. PCR-mediated gene replacement, targeting bkdF, one of avermectin's starter unit encoding genes in S. avermitilis, was performed to yield an oligomycin producer, BIB0423. The engineered strain produced oligomycin A at 2.3 mg/ml compared to the wild type strain at 0.1 mg/ml. This resulting mutant was genetically stable and should be useful for the industrial production of oligomycin.

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Cited by 5 publications

References 4 publications

Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer

Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer

A new strain of Streptomyces avermitilis produces high yield of oligomycin A with potent anti-tumor activity on human cancer cell lines in vitro

Enhancement and Selective Production of Oligomycin through Inactivation of Avermectin’s Starter Unit in Streptomyces avermitilis

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