Improvement of purine and pyrimidine antimetabolite-based anticancer treatment by selective suppression of mycoplasma-encoded catabolic enzymes

Liekens, Sandra; Bronckaers, Annelies; Balzarini, Jan

doi:10.1016/s1470-2045(09)70037-3

Cited by 27 publications

(24 citation statements)

References 56 publications

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“…Therefore we hypothesized that mycoplasmas and their metabolic impact on the tumor microenvironment may be of significance when optimizing cancer chemotherapy and that the administration of mycoplasma-directed antibiotics or specific inhibitors of mycoplasma-encoded enzymes may improve therapeutic outcome (34). Here, we report a severely compromised cytostatic activity of dFdC in mycoplasma-infected tumor cell cultures.…”

mentioning

confidence: 78%

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

Voorde

Sabuncuoğlu

Noppen

et al. 2014

Journal of Biological Chemistry

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125

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Background: Gemcitabine is used to treat solid tumors. Some mycoplasmas preferentially colonize tumors in patients. Results: Mycoplasma-encoded cytidine deaminase and pyrimidine nucleoside phosphorylase compromise the cytostatic/antitumor activity of gemcitabine in mycoplasma-infected tumor cell cultures and xenografts in mice. Conclusion: Tumor-associated mycoplasmas may decrease the therapeutic efficiency of gemcitabine. Significance: Current treatment of mycoplasma-infected tumors with gemcitabine may be suboptimal.

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mentioning

confidence: 78%

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

Voorde

Sabuncuoğlu

Noppen

et al. 2014

Journal of Biological Chemistry

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125

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“…Therefore, a controlled mycoplasma infection of tumor cell cultures in vitro may serve as an assay model to study the effect of prokaryotes on cancer chemotherapy. Previously, we showed that the cytostatic and antiviral activities of different thymidine and uridine analogs are dramatically decreased in mycoplasma-infected cell cultures as a result of the expression of a mycoplasma-encoded PyNP (Bronckaers et al, 2008;Liekens et al, 2009;Vande Voorde et al, 2012). In the present study, we report that the expression of a specific mycoplasma-encoded PNP may improve or diminish the cytostatic activity of purine nucleoside analogs, depending on the nature of the drug and its mechanism of cytostatic action.…”

Section: Introductionmentioning

confidence: 50%

Mycoplasma hyorhinis–Encoded Purine Nucleoside Phosphorylase: Kinetic Properties and Its Effect on the Cytostatic Potential of Purine-Based Anticancer Drugs

Voorde

Liekens

Balzarini

2013

Molecular Pharmacology

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A mycoplasma-encoded purine nucleoside phosphorylase (designated PNP Hyor ) has been cloned and characterized for the first time. Efficient phosphorolysis of natural 6-oxopurine and 6-aminopurine nucleosides was observed, with adenosine the preferred natural substrate (K m 5 61 mM). Several cytostatic purine nucleoside analogs proved to be susceptible to PNP Hyormediated phosphorolysis, and a markedly decreased or increased cytostatic activity was observed in Mycoplasma hyorhinis-infected human breast carcinoma MCF-7 cell cultures (MCF-7.Hyor), depending on the properties of the released purine base. We demonstrated an ∼10-fold loss of cytostatic activity of cladribine in MCF-7.Hyor cells and observed a rapid and complete phosphorolysis of this drug when it was exposed to the supernatant of mycoplasmainfected cells. This conversion (inactivation) could be prevented by a specific PNP inhibitor. These findings correlated well with the high efficiency of PNP Hyor -catalyzed phosphorolysis of cladribine to its less toxic base 2-chloroadenine (K m 5 80 mM). In contrast, the cytostatic activity of nucleoside analogs carrying a highly toxic purine base and being a substrate for PNP Hyor , but not human PNP, was substantially increased in MCF-7.Hyor cells (∼130-fold for fludarabine and ∼45-fold for 6-methylpurine-29-deoxyriboside). Elimination of the mycoplasma from the tumor cell cultures or selective inhibition of PNP Hyor by a PNP inhibitor restored the cytostatic activity of the purine-based nucleoside drugs. Since several studies suggest a high and preferential colonization or association of tumor tissue in cancer patients with different prokaryotes (including mycoplasmas), the data presented here may be of relevance for the optimization of purine nucleoside-based anticancer drug treatment.

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“…Persistent Mycoplasma infection induced malignant transformation of human cells, as shown in a recent study (Namiki et al ., 2009). Mycoplasma infection can reduce the effect of anticancer nucleoside analogues due to degradation by Mycoplasma enzymes (Liekens et al ., 2009). Therefore, it may be beneficial to treat Mycoplasma infection in cancer patients who receive nucleoside analogues as chemotherapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of thymidine kinase activity compensates for loss of thymidylate synthase activity in Mycoplasma pneumoniae

Wang

Hames

Schmidl

et al. 2010

Molecular Microbiology

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SummaryThymidylate, an essential building block of DNA, is synthesized either from deoxyuridylate by thymidylate synthase (TS) or thymidine (dT) by thymidine kinase (TK). Thymidylate kinase (TMPK) phosphorylates dTMP to dTTP. Thymidine phosphorylase (TP) catalyses reversible phosphorolysis of dT. Using transposon mutagenesis M. pneumoniae TS gene (thyA/MPN320) was interrupted and requirement of these enzymes was studied. We found that TK activity and transcript levels and TP activity, but not TMPK or TS activity, are growth-phase-regulated, with induction at the exponential growth phase and a decline after the stationary phase. Inactivation of thyA results in upregulation of TK transcript and a 10-fold increase in TK activity, reduced TMPK level and it had no effect on TP activity. The level of [ 3 H]-dT uptake and incorporation into DNA in the thyA mutant correlates with increases in TK activity, suggesting that dT uptake and metabolism is TK-dependent and that upregulation of TK activity in the thyA mutant compensates for the lack of ThyA activity. [ 3 H]-dU uptake was low compared with dT, and incorporation of radioactivity into DNA in the thyA mutant indicates the presence of an alternative TS. Our results suggest that TK and TMPK are potential targets for the development of Mycoplasma-specific antibiotics.

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Improvement of purine and pyrimidine antimetabolite-based anticancer treatment by selective suppression of mycoplasma-encoded catabolic enzymes

Cited by 27 publications

References 56 publications

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

Mycoplasma hyorhinis–Encoded Purine Nucleoside Phosphorylase: Kinetic Properties and Its Effect on the Cytostatic Potential of Purine-Based Anticancer Drugs

Upregulation of thymidine kinase activity compensates for loss of thymidylate synthase activity in Mycoplasma pneumoniae

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