Low-dose Doxorubicin May Overcome Leukemia Resistance

- Apr 25, 2020-

In a new study published online in Nature-Cell Biology on April 20th, Chinese and American researchers reported a new method that might overcome drug resistance in leukemia: the use of low doses is widely used to treat a variety of Cancer chemotherapy drug doxorubicin.

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Although traditional chemotherapy or radiotherapy for cancer has a certain effect in the early stage of treatment, the resistance caused by it often leads to cancer recurrence. In recent years, anti-immune screening gene therapy (immunotherapy) has become a new method of treating cancer, but immunotherapy has only shown good results in limited types of cancer, and a large proportion of patients still relapse after immunotherapy. Therefore, the basic mechanism of drug resistance including immune escape is a fundamental problem to be solved urgently.

Previously, researchers hypothesized that inhibiting Akt phosphorylation of β-catenin would reduce the former's activity and inhibit leukemia. To test this hypothesis, researchers from the US Stowers Medical Research Institute, the University of Kansas, and Tsinghua University in China conducted high-throughput screening of chemical libraries approved by the US Food and Drug Administration and identified 24 lead compounds. As a result, it was found that the widely used chemotherapeutic drug doxorubicin specifically inhibited the interaction between Akt and β-catenin at low doses.

The researchers used low-dose doxorubicin together with the clinically used chemotherapeutic agent nairabine to treat double-mutant mice. They observed that chemotherapy can effectively eliminate the majority of leukemia cells, but induce the expansion of a small number of leukemia stem cells. In contrast, low-dose doxorubicin had no effect on leukemia cells, but reduced leukemia stem cells. The combination of low-dose doxorubicin and nairabine has the best effect. To further confirm the inhibitory effect, the researchers collaborated in a small clinical trial to test the response of 10 to 20 patients with acute myeloid leukemia who had developed resistance to chemotherapy to daunorubicin. The results showed that 50% of patients with acute myeloid leukemia who already had chemotherapy resistance responded to low-dose daunorubicin and significantly reduced the number of leukemia stem cells.

The study also found that the inhibitory effect of low-dose doxorubicin on leukemia stem cells depends on the anti-cancer T cells expressing CD8. Therefore, the new treatment not only targets leukemia stem cells directly, but also exposes them to activated immune responses. (Bioon.com)