According to the research, published in Nature Cell Biology, targeted doses of doxorubicin could potentially inhibit the interaction between two molecular pathways that work together to encourage tumor growth.
Doxorubicin
Researchers from the Stowers Institute for Medical Research, Children’s Mercy Kansas City and The University of Kansas Cancer Center published a study on April 20 detailing a new strategy that may help overcome drug resistance in leukemia.
According to the research, published in Nature Cell Biology, targeted doses of doxorubicin could potentially inhibit the interaction between two molecular pathways that work together to encourage tumor growth.
John M. Perry, PhD, a researcher with the Children’s Mercy Research Institute at Children’s Mercy, stated that low doses of doxorubicin seemed to stimulate the immune system, in contrast with typical clinical doses.
Stowers Institute Investigator Linheng Li and Research Specialist Xi He were able to show in their research that the protein kinase Akt could enhance Wnt signaling via phosphorylating beta-catenin. In turn, tumorigenesis was promoted within the gut.
Perry then turned to a mouse model with genetic modifications of the Wnt/beta-catenin and PI3K/Akt pathways, and discovered that the two pathways work together to drive stem cell renewal. This resulted in excessive blood-forming stem cell production, but instead of just expanding stem cells, the permanent activation of the pathways ended with the mice developing leukemia. Using this information, the researchers began to focus on how to inhibit the interaction between those pathways to target leukemia stem cells.
Typically, drugs that directly target the Wnt/beta-catenin or PI3K/Akt pathways eventually fail because the cancer cells become resistant to them.
“Our idea was to find a drug with the goal of blocking the interaction between Wnt/beta-catenin and PI3K/Akt and reduce the toxicity,” Li said.
The researchers carried out drug screening, which revealed that doxorubicin was the most effective drug for inhibiting the interaction between the two pathways. They also turned to samples collected from pediatric leukemia patients at Children’s Mercy, which helped them better understand whether low-dose doxorubicin treatment could improve survival rates and reduce leukemia development.
“We found that mice receiving patient sample transplants with therapy-resistant leukemia stem cells rapidly developed leukemia, but low-dose doxorubicin treatment improved survival by reducing leukemia stem cells,” Perry said. “However, mice receiving patient sample transplants that did not contain therapy-resistant leukemia stem cells did not respond to low-dose doxorubicin treatment. These results showed that chemoresistant leukemia stem cells from patients could be functionally reduced with low-dose doxorubicin treatment, at least in an in vivo animal model assay.”
Li added that the research could eventually help others develop a more effective strategy to overcome cancer therapy resistance.
This is not the first time that researchers have uncovered a way to attack cancer with low doses of a drug. Scientists from Mater Research – The University of Queensland, announced earlier in April that they found they could overcome chemotherapy resistance in an ovarian cancer subtype by using low doses of 2-deoxy-D-glucose.
At minimal levels, Doxorubicin appeared to significantly improve the effectiveness of chemotherapy in treating clear cell ovarian cancer tumor cells, according to the Translational Research Institute. Their work, which was published in the journal Cancers, may warrant other researchers’ desire to launch a clinical trial to learn more about the potential of 2-deoxy-D-glucose.
Earlier in April, scientists also discovered a new method for inhibiting the protein HSP72, according to the Institute of Cancer Research. This protein is known for helping cancer cells survive and resist treatment. One day, researchers may be able to use this method to develop drugs that directly target HSP72.
