6-Thioguanine: A Drug With Unrealized Potential for Cancer Therapy

Munshi, Pashna N.; Lubin, Martin; Bertino, Joseph R.

doi:10.1634/theoncologist.2014-0178

Cited by 83 publications

(58 citation statements)

References 38 publications

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“…Inhibitors identified in virtual screening included Food and Drug Administration-approved drugs used to treat cardiovascular disease, certain types of cancer, autoimmune diseases, anorexia, cachexia, and weight loss associated with cancer and AIDS (1, 48–50). Emerging evidence indicates that in addition to regulating insulin signaling, cytoskeleton remodeling, and receptor endocytosis (51), SHIP2 is implicated in the development and progression of certain types of cancer (52).…”

Section: Discussionmentioning

confidence: 99%

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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Metformin, the first-line drug to treat type 2 diabetes (T2D), inhibits mitochondrial glycerolphosphate dehydrogenase in the liver to suppress gluconeogenesis. However, the direct target and the underlying mechanisms by which metformin increases glucose uptake in peripheral tissues remain uncharacterized. Lipid phosphatase Src homology 2 domain-containing inositol-5-phosphatase 2 (SHIP2) is upregulated in diabetic rodent models and suppresses insulin signaling by reducing Akt activation, leading to insulin resistance and diminished glucose uptake. Here, we demonstrate that metformin directly binds to and reduces the catalytic activity of the recombinant SHIP2 phosphatase domain in vitro. Metformin inhibits SHIP2 in cultured cells and in skeletal muscle and kidney of db/db mice. In SHIP2-overexpressing myotubes, metformin ameliorates reduced glucose uptake by slowing down glucose transporter 4 endocytosis. SHIP2 overexpression reduces Akt activity and enhances podocyte apoptosis, and both are restored to normal levels by metformin. SHIP2 activity is elevated in glomeruli of patients with T2D receiving nonmetformin medication, but not in patients receiving metformin, compared with people without diabetes. Furthermore, podocyte loss in kidneys of metformin-treated T2D patients is reduced compared with patients receiving nonmetformin medication. Our data unravel a novel molecular mechanism by which metformin enhances glucose uptake and acts renoprotectively by reducing SHIP2 activity.—Polianskyte-Prause, Z., Tolvanen, T. A., Lindfors, S., Dumont, V., Van, M., Wang, H., Dash, S. N., Berg, M., Naams, J.-B., Hautala, L. C., Nisen, H., Mirtti, T., Groop, P.-H., Wähälä, K., Tienari, J., Lehtonen, S. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity.

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Section: Discussionmentioning

confidence: 99%

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Polianskyte-Prause¹,

Tolvanen²,

Lindfors³

et al. 2018

FASEB j.

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“…Up to the present, hundreds of 6MP and 6TG related studies have been published every year, including metabolism, pharmacokinetics and dosage as well as their use in various therapies that target cancers, rheumatoid arthritis, systemic lupus erythematosus and Crohn's disease (Karran and Attard, 2008). 6TG has recently been proposed as a means of treating a wide variety of cancers that have a high frequency of homozygous deletion of the gene encoding methylthioadenosine phosphorylase, which include leukemia, glioblastoma, lung cancer, pancreatic, squamous cell carcinoma and others (Munshi et al, 2014). In addition, 6MP and its pro-drug, azathioprine, have also been used for many years as an immunosuppressant when treating organ transplant recipients (Karran and Attard, 2008).…”

Section: Discussionmentioning

confidence: 99%

Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus

Cheng¹,

et al. 2015

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Middle East respiratory syndrome coronavirus (MERS-CoV) is a new highly pathogenic human coronaviruses that emerged in Jeddah and Saudi Arabia and has quickly spread to other countries in Middle East, Europe and North Africa since 2012. Up to 17 December 2014, it has infected at least 938 people with a fatality rate of about 36% globally. This has resulted in an urgent need to identify antiviral drugs that are active against MERS-CoV. The papain-like protease (PL(pro)) of MERS-CoV represents an important antiviral target as it is not only essential for viral maturation, but also antagonizes interferon stimulation of the host via its deubiquitination activity. Here, we report the discovery that two SARS-CoV PL(pro) inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG), as well as the immunosuppressive drug mycophenolic acid, are able to inhibit MERS-CoV PL(pro). Their inhibition mechanisms and mutually binding synergistic effect were also investigated. Our results identify for the first time three inhibitors targeting MERS-CoV PL(pro) and these can now be used as lead compounds for further antiviral drug development.

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“…One report showed that MTAP abrogates phosphoribosylation conversion of 6‐TG to a toxic derivative (Munshi et al ., 2014). Interestingly, another report revealed that the p16 gene is often lost along with the MTAP gene in pancreatic cancer (Lubin and Lubin, 2009; Munshi et al ., 2014). RT‐PCR and Western blot analysis indicated that MTAP was expressed in HPDE and 34 629 cells (which showed the highest IC 50 among four PDAC cell lines; Fig.…”

Section: Resultsmentioning

confidence: 99%

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

et al. 2018

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Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive‐compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose‐dependent analysis revealed three compounds with a tumor cell‐specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6‐thioguanine (6‐TG) showed an IC50 of 0.39–1.13 μm toward PDAC cells but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6‐TG. Lastly, we used a patient‐derived xenograft model to confirm that 6‐TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6‐TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

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6-Thioguanine: A Drug With Unrealized Potential for Cancer Therapy

Cited by 83 publications

References 38 publications

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity

Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

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