Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors.
May 22, 2013

Acute myeloid leukemia (AML) is characterized by the proliferation of immature, non-functional blood cells in the bone marrow and blood, thereby reducing the number of healthy blood cells circulating in a person's body. Leukemic cells can be eliminated using conventional chemotherapeutics, however in many cases, the cancer returns after treatment. Consequently, scientists are investigating new, more effective drugs to treat AML (1,2).
In Sukhai M.A., Prahba S., et al. (2013), a group of scientists led by Dr. Mahadeo Sukhai and Dr. Swayam Prabha from Dr. Aaron Schimmer's lab (OCI), discovered that mefloquine, an antimicrobial used to clear malarial infections, selectively kills AML cells. Mefloquine's anti-leukemic activity was first demonstrated in a screen of on- and off-patent drugs that assessed their ability to kill different kinds of leukemia cells. Under Dr. Sukhai's guidance, scientists performed a series of assays on cell cultures and in mice, showing that mefloquine prevented the growth and proliferation of leukemic cells, but not that of normal cells.

Next, to determine the molecular mechanism underlying mefloquine's toxicity, the team of scientists used two very different high-throughput screens—a yeast genomic screen known as haploinsufficiency profiling (the “HIP” assay), and a combinatorial chemical screen to identify drugs that acted synergistically with mefloquine to kill leukemic cells. Both screens yielded similar results and allowed Dr. Sukhai to formulate the hypothesis that mefloquine killed AML cells by disrupting lysosomes, cellular compartments responsible for breaking down and recycling proteins and organelles. Dr. Prabha validated this hypothesis by showing that mefliquone treatment caused AML cells to leak lysosomal enzymes—proteases, lipases and hydrolase—into the cytoplasm, causing cells to digest themselves and die. It is not clear why leukemic cells are more susceptible to mefloquine than normal cells; however, Dr. Sukhai observed that leukemic cells have enlarged lysosomes and overproduce many proteins involved in lysosome biogenesis. These results suggest that lysosmal disruption may be a novel therapeutic strategy for treating AML that warrants further investigation.

1. Ferrarra F. and Schiffer C.A. 2013. Lancet 381: 484-95
2. American Cancer Society:

Source: ORT Times, May 2013
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