The same mechanism that predisposes women to a higher risk of ovarian cancer may also open the door to successful treatment using auranofin, a repurposed agent for rheumatoid arthritis (RA), according to a new study published in Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis.

“Using drugs such as auranofin to treat cancer is highly promising since they are readily available and their pharmacological and toxicological properties are well documented,” explained lead author Awadhesh Jha, PhD, Professor of Toxicology and Associate Head of Research in the School of Biological Sciences at Plymouth University in Plymouth, United Kingdom.

A number of in vitro and animal studies conducted since 1985 have shown strong cytotoxic effects of auranofin to various types of chemotherapy-resistance cancers, including leukemia, lymphoma, and gastrointestinal, lung, and ovarian cancers.1 Auranofin is currently undergoing phase 2 clinical trials for the treatment of recurrent epithelial ovarian cancer, where the influence of the breast cancer 1 (BRCA1) gene may enhance its cytotoxic efficacy.2


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Cytotoxic Properties of Auranofin

Although auranofin was originally approved by the US Food and Drug Administration as a disease-modifying antirheumatic agent (DMARD) for the treatment of RA, its anti-inflammatory actions are mediated through disruption of cellular reduction/oxidation mechanisms of the enzyme thioredoxin reductase, rendering cells vulnerable to irreversible damage from chemotherapeutic agents.

Auranofin demonstrates a second cytotoxic mechanism through inhibition of the ubiquitin-proteasome system, a critical manager of cellular health through cycle regulation, protein degradation, gene expression, and DNA repair, and which may play a greater role in the survival of cancer cells than other types of cells.3,4

These combined mechanisms contribute to potent effects in inducing selective apoptosis of cancer cells through alternative pathways. The implications for the use of auranofin to treat cancers that are resistant to chemotherapies—such as lung and ovarian cancer—have prompted new investigations into this well-known drug.1

BRCA1 Enhances Sensitivity to Auranofin

The Plymouth University study was undertaken to evaluate the compounded  mechanism of BRCA1 protein deficiency in promoting drug sensitivity to auranofin for benefits in chemotherapy-resistant ovarian cancer. The BRCA1 protein is critical to DNA repair; deficiency in BRCA1 is associated with the development of malignancies of the breast and ovaries. Ironically, BRCA1 deficiency also leads to irreparable double-strand breaks, providing a therapeutic window for increased sensitivity to auranofin.5,/p>

“Studies carried out with cells grown under laboratory conditions showed faults in the BRCA1 gene, rendering these cells more vulnerable to auranofin compared to ovarian cancer cells with normal BRCA1 genes,” Dr Jha said.

Two ovarian cell lines (OVCAR5 and SKOV3) were treated with auranofin, after which BRCA1 expression was depleted using small interfering RNA (siRNA). Cell survival was significantly reduced in both cells lines in the presence of BRCA1 depletion: 35% and 37% decreased survival in SKOV3 auranofin-treated cells at doses of 0.05 µm and 1 µm, respectively, and 32%, 44%, and 47% decreases in survival of OVCAR5 auranofin-treated cells at doses of 0.05 µm, 1 µm, and 2 µm, respectively, compared to nondepleted control cells.

“It suggests that auranofin has the potential to be considered for future clinical studies to treat such ovarian cancers, and this could serve as the springboard to use other available drugs [that] are not used as chemotherapeutic drugs,” Dr Jha reported.

References

1. Roder CA, Thomson MJ.  Auranofin: repurposing an old drug for a golden new age.  Drugs. 2015;15:13-20.

2.  US National Institutes of Health. Auranofin in Treating Patients with Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer.   https://clinicaltrials.gov/ct2/show/NCT01747798. Accessed January 25, 2016

3.  Chen X, Shi X, Zhao C, et al. Anti-rheumatic agent auranofin-induced apoptosis in chronic myeloid leukemia cells resistant to imitinib through both Bcr/Abl-dependent and independent mechanisms. Oncotarget. 2014;5:9118-9132.

4.  Liu N, Li X, Huang H, et al. Clinically used antirheumatic agent auranofin is a proteasomal deubinquinase inhibitor and inhibits tumor growth. Oncotarget. 2014;5:5453-5471.

5.  Oommen D, Yiannakis D, Jha AW. BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin. Mutation Research. 2016;784:8-15.