Chaetocin synergistic with TKIs against CML cells

Nov 14 2014

By Shreeya Nanda, Senior medwireNews Reporter

Chaetocin, a mycotoxin that increases oxidative stress, can complement the activity of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML) by overcoming innate resistance mediated by secreted bone marrow stromal cytokines and growth factors (BMSFs), researchers report.

The authors explain that CML–leukaemic stem cells (CML–LSCs), which exhibit innate resistance to TKIs, are crucial for the maintenance of CML. And add that BMSFs are implicated in this innate resistance, and are also known to increase the levels of reactive oxygen species (ROS).

“Higher ROS levels in CML-LSCs exposed to BMSFs might render them susceptible to ROS-mediated damage by exogenous ROS-generating agents”, hypothesises the team in Oncogenesis.

C Ron Geyer (University of Saskatchewan, Saskatoon, Canada) and colleagues used cells isolated from a BCR–ABL-positive mouse model of CML blast crisis (CML–LSK cells) to assess the effects of chaetocin, a ROS-generating agent, administered on its own and in combination with the TKI imatinib, on cell growth.

Chaetocin significantly reduced the viability and colony forming capacity of CML–LSK cells, and increased apoptosis. These effects of chaetocin were enhanced in the presence of BMSFs.

Moreover, treatment with both chaetocin and imatinib overcame BMSF-mediated imatinib resistance, and resulted in increased cytotoxicity and apoptosis induction as well as a complete loss of colony formation.

Although treatment with either chaetocin or BMSFs resulted in increased ROS levels in CML–LSKs, when the two were used in combination, ROS levels were significantly higher than when either was used alone. Interestingly, chaetocin-mediated cytotoxicty was inhibited when the cells were pretreated with an antioxidant, N-acetyl-cysteine.

This “strongly suggested” that chaetocin activity against CML–LSKs, and its potentiation by BMSFs, was mediated by the increased ROS, say the researchers.

Geyer and colleagues also investigated the effect of chaetocin on CML–LSK self-renewal in vivo. CML–LSKs isolated from mice with CML were exposed to chaetocin, either in the presence or absence of BMSFs, and transplanted into secondary recipients. CML–LSKs pretreated with chaetocin increased the disease latency period more than twofold when compared with transplantation of untreated cells or CML–LSKs exposed to BMSFs.

Additionally, treatment with chaetocin and BMSFs significantly prolonged survival time compared with chaetocin alone.

The authors conclude: “[C]haetocin may serve as a broadly applicable codrug for overcoming innate TKI resistance in a variety of hematological and nonhematological cancers.”

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