Researchers from Rice University and the University of Texas MD Anderson Cancer Center have discovered potential new drugs that work in concert with other drugs to deliver a deadly one-two punch to leukemia.
The potential drugs are still years away from being tested in cancer patients, but a recently published study in the journal Leukemia highlights their promise and the innovative methods that led to their discovery.
In previous studies, the research groups of Rice biochemist Natasha Kirienko and MD Anderson physician-scientist Marina Konopleva screened some 45,000 small-molecule compounds to find a few that targeted mitochondria. In the new study, they chose eight of the most promising compounds, identified between five and 30 closely related analogs for each and conducted tens of thousands of tests to systematically determine how toxic each analog was to leukemia cells, both when administered individually or in combination with existing chemotherapy drugs like doxorubicin.
“One of the big challenges was to establish optimal conditions and doses for testing on both cancer cells and healthy cells,” said study lead author Svetlana Panina, a researcher at the University of Texas at Austin who conducted the research during her postdoctoral studies at Rice. “The results from our previously published cytotoxicity assay were helpful, but very little is known about these small-molecule compounds. None of them had been thoroughly described in other studies, and we had to essentially start from scratch to determine how much to use, what they do in cells, everything. All the doses and treatment conditions had to be adjusted by multiple preliminary experiments.”
In prior work, Kirienko’s lab had shown the eight compounds targeted energy-producing machinery inside cells called mitochondria. Dozens to thousands of mitochondria are at work every minute in every living cell, and like all machines, they wear out with use. The eight compounds induce mitophagy, the housekeeping routine cells use to decommission and recycle mitochondria that are past their prime.
During times of extreme stress, cells can temporarily forgo mitophagy to get an emergency energy boost. Cancer is notorious for hijacking these sorts of programs to fuel pathological growth. For example, previous research has shown leukemia cells have far more damaged mitochondria than healthy cells and are also more sensitive to mitochondrial damage than healthy cells.
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