Mitophagy against leukemia
Researchers from Rice University and the University of Texas have discovered a compound that, together with well-known drugs, strikes cancer cells of patients suffering from leukemia.
In their previous work, the researchers screened about 45,000 low molecular weight compounds to find those that target mitochondria. In the new study, they selected eight of the most promising compounds, identified from 5 to 30 related analogues for each and conducted tens of thousands of tests, systematically determining how toxic each analog is for leukemia cells both when administered individually and in combination with existing chemotherapeutic drugs, in particular, with doxorubicin.
One of the major obstacles in the course of the study was to determine the optimal conditions and doses for testing on cancer and healthy cells, since very little was known about these low-molecular compounds before.
Hundreds of mitochondria work in every living cell every minute, and, like all mechanisms, they wear out over time. The experimental compounds selected by the researchers induce mitophagy, a natural process of recycling old mitochondria.
During severe stress, cells suspend mitophagy to get an emergency boost of energy. In oncological diseases, cancer cells use such programs to maintain pathological growth. Thus, leukemic cells have much more damaged mitochondria and are more sensitive to their damage than healthy cells.
The researchers concluded that drugs that enhance mitophagy can weaken leukemic cells and make them susceptible to chemotherapy. And indeed, six out of eight low-molecular compounds were fatal to leukemia cells. To study them in more detail, the group considered related compounds and their action in various combinations.
There is a parameter that quantifies the interaction between drugs – the synergy coefficient. A negative value of the coefficient indicates that the drugs are antagonistic, zero indicates no effect, and positive numbers indicate positive interactions. Values above 10 are considered a synergistic effect.
One of the currently prescribed combinations of chemotherapeutic drugs – doxorubicin and cytarabine — has a synergy coefficient of 13. The group's experiments showed that several mitophagy-inducing compounds were significantly more synergistic with doxorubicin, and a compound called PS127B had a coefficient of 29.
The researchers tested the toxicity of mitophagy-inducing compounds and combinations against acute myeloid leukemia (AML) cells. They then tested six of the most effective AML cell-killing compounds against other forms of leukemia and found that five of them were also effective against acute lymphoblastic leukemia (ALL) cells and chronic myeloid leukemia (CML) cells. Control studies have shown that all drugs that cause mitophagy cause much less harm to healthy cells.
In other experiments, the researchers tested PS127E using a xenograft model from a patient (human cancer cells implanted in an immunodeficient or humanized mouse), also called a "clinical trial on mice." The models were exposed to a drug or a combination of drugs. The compound PS127E has shown the ability to effectively destroy human AML cells in mice.
New studies are needed to clarify the dose, as well as to test the effectiveness in different types of AML.
Article by S.Panina et al. The novel mitochondria-targeting compounds selectively kill human leukemia cells is published in the journal Leukemia.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Rice University: Researchers discover new leukemia-killing compounds.