Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines.

Maia Cabrera,Federico Remes Lenicov,Natalia Fernández,Pablo Lorenzano Menna,Carlos Davio,Georgina Cardama,Nazareno Gonzalez,Emiliana Echeverria

doi:10.18632/oncotarget.21533

Abstract

Rac1 GTPase has long been recognized as a critical regulatory protein in different cellular and molecular processes involved in cancer progression, including acute myeloid leukemia. Here we show the antitumoral activity of ZINC69391 and 1A-116, two chemically-related Rac1 pharmacological inhibitors, on a panel of four leukemic cell lines representing different levels of maturation. Importantly, we show that the main mechanism involved in the antitumoral effect triggered by the Rac1 inhibitors comprises the induction of the mitochondrial or intrinsic apoptotic pathway. Interestingly, Rac1 inhibition selectively induced apoptosis on patient-derived leukemia cells but not on normal mononuclear cells. These results show the potential therapeutic benefits of targeting Rac1 pathway in hematopoietic malignancies.

Highlights

Rho-GTPases are molecular switches that cycle between an inactive GDP-bound form and an active GTP-bound form
ZINC69391 is a first generation small molecule that was identified as a Rac1-guanine nucleotide exchange factors (GEFs) interaction inhibitor, using a docking-based virtual library screening approach
ZINC69391 was able to inhibit several Rac1-GEF interactions, which were associated to antiproliferative effects, cell cycle arrest and migration inhibition of highly aggressive breast cancer cell lines [18]

Summary

Introduction

Rho-GTPases are molecular switches that cycle between an inactive GDP-bound form and an active GTP-bound form. This cycle is closely regulated by guanine nucleotide exchange factors (GEFs) that catalyze nucleotide exchange and mediate activation [1]; and GTPase-activating proteins (GAPs), that stimulate GTP hydrolysis and inactivate the GTPase [2]. Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by an accumulation of immature hematopoietic stem cells in the bone marrow [7, 8]. AML is the most common type of leukemia in adults with lowest survival rate of all leukemias

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Conclusion