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Auranofin: repurposing an old drug for a golden new age.

ABSTRACT: Drug discovery, development and registration is an expensive and time-consuming process associated with a high failure rate [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013), Woodcock and Woosley (Annu Rev Med 59:1-12, 2008)]. Drug 'repurposing' is the identification of new therapeutic purposes for already approved drugs and is more affordable and achievable than novel drug discovery [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013)]. Auranofin is a drug that is approved for the treatment of rheumatoid arthritis but is being investigated for potential therapeutic application in a number of other diseases including cancer, neurodegenerative disorders, HIV/AIDS, parasitic infections and bacterial infections [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029-2035, 2013)]. The main mechanism of action of auranofin is through the inhibition of reduction/oxidation (redox) enzymes that are essential for maintaining intracellular levels of reactive oxygen species. Inhibition of these enzymes leads to cellular oxidative stress and intrinsic apoptosis [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013), Fan et al. (Cell Death Dis 5:e1191, 2014), Fiskus et al. (Cancer Res 74:2520-2532, 2014), Marzano et al. (Free Radic Biol Med 42:872-881, 2007)]. Drugs such as auranofin that have already been approved for human use [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029-2035, 2013)] can be brought into clinical use for other diseases relatively quickly and for a fraction of the cost of new drugs.

SUBMITTER: Roder C

PROVIDER: S-EPMC4359176 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThere is increasing pre-clinical and clinical evidence that metformin, a commonly used diabetes medication, has a protective effect in cancer. The aim of this review is to discuss metformin's anti-cancer molecular mechanisms of action and to summarize the current literature demonstrating metformin's potential in gynecologic cancer prevention and treatment.MethodsA PubMed search was conducted combining the keywords "metformin" with "neoplasm", "uterine neoplasms", "ovarian neoplasms", and "uterine cervical neoplasms". Studies published in English between 1994 and 2014 were included.ResultsPre-clinical studies in endometrial, ovarian, and cervical cancer suggest that metformin inhibits the growth of cancer cells. The primary molecular mechanism mediating this effect appears to be the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of mammalian targets of rapamycin (mTOR). The pre-clinical findings are augmented by clinical studies indicating that metformin use is associated with a reduced risk of cancer and improved survival in diabetic women with ovarian and endometrial cancers. No clinical analyses have evaluated metformin use and cervical cancer. Overall, the data showing a favorable effect of metformin is strongest for endometrial and ovarian cancer and prospective clinical testing is ongoing in these two malignancies.ConclusionsNumerous clinical studies have reported an association between metformin use by diabetic patients and improved outcomes in gynecologic cancers. In addition, pre-clinical reports have identified plausible biological mechanisms to explain the molecular mechanism of action of metformin in cancer. However, the most important question remains unanswered: Will metformin be effective against cancer in patients without diabetes? Until this question is answered with prospective clinical testing, the role of metformin in the treatment or prevention of gynecologic malignancies remains theoretical and the clinical use of metformin as a cancer therapeutic is experimental.

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Auranofin: repurposing an old drug for a golden new age.

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