Abstract
Chronic lymphocytic leukemia (CLL) is a malignancy disease characterized by the expansion of CD5+ B-1 cells. The NZB mouse model of CLL shows similarities to human CLL, has age-associated increase in malignant B-1 clones and decreased expression of miR-15a/16. It was demonstrated that systemic lentiviral delivery of miR-15a/16 ameliorates disease manifestations in this mouse model. Nowadays, new therapeutic approaches have been focus on miRNA in cancer cells. Natural compounds like quercetin can modulate these miRNAs, consequently, suppress oncogenes or stimulate tumor suppressor genes by altering miRNA expressions. Here we investigate the effects of quercetin on miRNA15a/16 expression by radio-resistant B-1 cells. It has been described that a small percentage of B-1 cell survives to irradiation in vitro, and these cells show similarities to B-CLL cells. In these cells, the level of miR15a/16 is diminished and Bcl-2 is overexpressed. Quercetin treatment restore both, miR15a/16 and Bcl-2, to normal levels. Furthermore, transference of radioresistant B-1 cells to NOD/SCID mice causes an expansion of this population and also a migration to the liver. However, after quercetin treatment, even radioresistant B-1 cells are not able to expand or disseminate in vivo, and the levels of miR15a/16 and Bcl-2 are also normalized. Our data support the hypothesis that quercetin is an important adjuvant molecule that acts on miRNA15a/16 level and leads cells more permissive to apoptosis. This work could help to design new approaches to therapy in CLL patients.
Highlights
Chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is clinically defined by the accumulation of dysfunctional CD5+ B cells [1]
At day 7, it is possible to observed a ~6 fold increase in control group, while irradiated B-1 cell pool increase ~14 fold. This result suggested that despite a large population of B-1 cells has been affected by irradiation, radio-resistant B-1 cells that survive in culture are resistant to apoptosis and able to proliferate
The apoptosis resistance is corroborated by elevated levels of Bcl-2 expression in radio-resistant B-1 cells (4 fold increased in comparison to control group – Figure 1F)
Summary
Chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is clinically defined by the accumulation of dysfunctional CD5+ B cells [1]. Lu D et al [4] described that at least six Wnt genes are overexpressed in CLL cells (Wnt 3, Wnt5b, Wnt, Wnt10a, Wnt, and Wnt16) and Fzd and its coreceptor LRP5 and 6 These authors show that partial inhibition of Wnt/pathway by R-etodolac shortened the in vitro survival of the CLL cells, contrariwise to SB-216763 www.oncotarget.com (GSK-3β inhibitor) treatment that enhances CLL survival. Other small molecule inhibitors (PKF115-584 and CGP049090) of Wnt/beta-catenin pathway succeed to diminish both in vitro and in vivo CLL survival [7]. These authors stated that these compounds did not affect health B cells in vitro and are well tolerated at doses that are effective for CLL cell killing in vivo in the CLL-like xenograft model in nude mice
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