Researchers at Rice University and MD Anderson have just discovered a potential punch that they hope could eliminate an insidious disease.

A recent study in the review Leukemia focuses on potential new drugs that, with the help of other drugs, can thwart leukemic cells.

Specifically, the rice biochemist Natasha Kirienko and physician-scientist MD Anderson Marina Konopleva screened some 45,000 small-molecule compounds to find a few that target mitochondria, according to Rice’s press materials.

In this innovative new study, the team selected eight of the most promising compounds, identified between five and 30 closely related analogs for each, and performed tens of thousands of tests to systematically determine each analog’s toxicity to leukemia cells. This was measured both when given individually or in combination with existing chemotherapy drugs like doxorubicin, a statement notes.

Previously, Kirienko’s lab had shown that the eight compounds targeted energy-producing machinery inside cells called mitochondria. Mitochondria, which function non-stop in every living cell, wear out with use. The eight selected compounds induce mitophagywhich can be described as how deficient and exhausted cells break down and recycle.

Notably, during times of extreme stress, cells can temporarily forego mitophagy for an emergency energy boost. Previous research has shown that leukemia cells have significantly more damaged mitochondria than healthy cells and are also more susceptible to mitochondrial damage than healthy cells.

Thus, Kirienko and Konopleva reasoned that drugs that induce mitophagy could weaken leukemic cells and make them more sensitive to chemotherapy. Synergy – the use of two or more drugs in treatment – is essential.

“The point of synergy is that there are concentrations, or dosages, where a single drug does not kill,” Kirienko said. “There is no death of healthy cells or cancer cells. But the administration of these same concentrations in combination can kill a considerable amount of cancer cells and still does not affect healthy cells.

The team tested the toxicity of its mitophagy-inducing compounds and combinations against cells of acute myeloid leukemia (AML), the most commonly diagnosed form of the disease. They then tested the six most effective anti-AML compounds against other forms of leukemia, finding that five were equally effective in killing acute lymphoblastic leukemia (ALL) cells and chronic myeloid leukemia (CML) cells. .

Studies have shown that all drugs that induce mitophagy cause significantly less damage to healthy cells.

Finally, the researchers tested one of the most effective mitochondria-targeting compounds, PS127E, using a cutting-edge technique called the patient-derived xenograft (PDX) model. Also called a “clinical mouse trial,” mice are implanted with cancer cells from a patient with leukemia. As the cells grow, the mouse is exposed to a drug or drug combination as a closer test than the cells of the treatment effect.

Importantly, PDX tests on one compound, PS127E, showed it to be effective in killing AML cells in mice, Rice notes, reporting promising news.

“Although this is very promising, we are still a long way from having a new treatment that we can use in the clinic,” Kirienko added. “We still have a lot to discover. For example, we need to better understand how drugs work in cells. We need to refine the dose that we think is best, and perhaps most importantly, we need to test on a wide variety of AML cancers. AML has many variations, and we need to know which patients are most likely to benefit from this treatment and which are not. Only after doing this work, which may take a few years, can we begin testing in humans.


This article was originally published on CultureMap.