Poster Presentation 30th Lorne Cancer Conference 2018

Targeting the Thioredoxin System to Overcome Hypoxia-Induced and Acquired Imatinib Resistance in Chronic Myeloid Leukaemia (#140)

Erin Clapper 1 , Kathryn F Tonissen 1 2 , Giovanna Di Trapani 1
  1. School of Natural Sciences, Griffith University, Nathan, QLD, Australia
  2. Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia

Chronic myeloid leukaemia (CML) is a cancer of granulocytes and is caused by a chromosomal translocation between chromosomes 9 and 22. This results in the production of a fusion oncoprotein known as bcr-abl, which activates various cell signalling pathways, leading to cancer. Currently, CML is treated with specific inhibitors of bcr-abl such as imatinib, however, drug resistance is a major concern in the treatment of CML. The inhibition of the thioredoxin (Trx) system is currently being studied as a means to combat drug resistance in various cancers. This study aimed to determine if the TrxR1 inhibitor, auranofin, is able to overcome imatinib resistance in CML.

It was observed that auranofin effectively induced apoptosis in CML cells that were resistant to imatinib. The primary causes of this apoptosis were the decrease in the activity of TrxR1 and the subsequent increase in the levels of reactive oxygen species (ROS). The increase in ROS levels was then observed to inhibit the mRNA expression levels of bcr-abl. This was observed to downregulate the Trx system. This study also supported the hypothesis that bcr-abl protein levels are suppressed in hypoxia. This observation is problematic for the treatment of CML, as this means that current CML treatments are ineffective in hypoxic environments such as the bone marrow. However, auranofin was still able to induce apoptosis in CML cells cultured in hypoxia, as the inhibition of the Trx system resulted in the downregulation of a hypoxia dependent cell survival pathway, known as the hypoxia inducible factor 1α (HIF-1α) pathway.