Oxidative Stress a Therapeutic Target to Overcome Cancer Cell Protection in CLL
Study findings suggest that pathways regulating redox homeostasis are suitable therapeutic targets that can overcome microenvironmental protection of cancer cells in patients with chronic lymphocytic leukemia (CLL; Leukemia. 2020;34[1]:115-127).
“[CLL] cells depend on microenvironmental non-malignant cells for survival,” wrote Deyan Yordanov Yosifov, MD, Department of Internal Medicine III, Ulm University, Germany, and co-investigators, who compared the transcriptomes of primary CLL cells that were or were not co-cultured with protective bone marrow stromal cells (BMSCs).
The comparison showed that the most significant dysregulation occurs in oxidative phosphorylation, mitochondrial function, and hypoxic signaling in non-protected CLL cells, with changes peaking at 6 to 8 hours, directly ahead of apoptosis induction.
“A subset of CLL patients displayed a gene expression signature resembling that of cocultured CLL cells and had significantly worse progression-free and overall survival,” the investigators said.
As a follow-up to these findings, they used relevant transcriptomic data from the Connectivity Map database to identify drugs blocking BMSC-mediated support.
Ultimately, Dr Yosifov and colleagues observed a correlation between the transcriptomic signatures of the cardiac glycoside ouabain and the ipecac alkaloids emetine and cephaeline. Both of these compounds were deemed to be highly active against protected primary CLL cells by blocking HIF-1α and disturbing intracellular redox homeostasis.
Emetine was evaluated in a murine model of CLL and led to a decrease in CLL cells in peripheral blood, spleen, and bone marrow, recovery of hematologic parameters, and doubling of median survival (31.5 vs 15 days; P = .0001).
“Pathways regulating redox homeostasis are thus therapeutically targetable mediators of microenvironmental support in CLL cells,” Dr Yosifov et al concluded.—Hina M. Porcelli
