Activity of BKM120 and BEZ235 against Lymphoma Cells.

Monica Civallero,Samantha Pozzi,Paola Ferri,Stefano Sacchi,Alessia Bari,Maria Cosenza

doi:10.1155/2015/870918

Monica Civallero, Samantha Pozzi + Show 4 more

Open Access

https://doi.org/10.1155/2015/870918

Copy DOI

Abstract

Non-Hodgkin lymphomas encompass a heterogeneous group of cancers, with 85–90% arising from B lymphocytes and the remainder deriving from T lymphocytes or NK lymphocytes. These tumors are molecularly and clinically heterogeneous, showing dramatically different responses and outcomes with standard therapies. Deregulated PI3K signaling is linked to oncogenesis and disease progression in hematologic malignancies and in a variety of solid tumors and apparently enhances resistance to antineoplastic therapy, resulting in a poor prognosis. Here, we have evaluated and compared the effects of the pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 on mantle, follicular, and T-cell lymphomas. Our results suggest that BKM120 and BEZ235 can effectively inhibit lymphoma cell proliferation by causing cell cycle arrest and can lead to cell death by inducing apoptosis and autophagy mediated by ROS accumulation. Despite great advances in lymphoma therapy after the introduction of monoclonal antibodies, many patients still die from disease progression. Therefore, novel treatment approaches are needed. BKM120 and BEZ235 alone and in combination are very effective against lymphoma cells in vitro. If further studies confirm their effectiveness in animal models, they may be promising candidates for development as new drugs.

Highlights

The phosphatidylinositol 3-kinase [PI3K] signaling pathway plays important roles in many physiological functions, including cell cycle progression, differentiation, survival, motility, apoptosis, autophagy, and protein synthesis [1,2,3,4]
PI3K activation leads to phosphorylation of AKT on Thr308, which in turn activates the mammalian target of rapamycin, a distal element of the PI3K/AKT/mTOR pathway [5]. mTOR is a serine/threonine kinase that encompasses two distinct complexes—mTORC1 and mTORC2—that differ structurally and in substrate specificity and functionally [6]. mTORC1 induces cell growth in response to nutrients and growth factors by regulating the translational regulators S6K1 and 4E-BP1. mTORC2 mediates cell proliferation and survival by phosphorylating AKT on Ser473, facilitating its full activation [7,8,9,10]
To determine the IC50 values and the effects of the drugs on cell viability, lymphoma cell lines were cultured with increasing concentrations of BKM120 (0.5–15 μM) and BEZ235 (0.5–50 nM) for 24 and 48 hours

Summary

Introduction

The phosphatidylinositol 3-kinase [PI3K] signaling pathway plays important roles in many physiological functions, including cell cycle progression, differentiation, survival, motility, apoptosis, autophagy, and protein synthesis [1,2,3,4]. MTORC2 mediates cell proliferation and survival by phosphorylating AKT on Ser473, facilitating its full activation [7,8,9,10]. The PI3K/Akt/mTOR pathway integrates survival signals from extracellular and intracellular stimuli to promote cell growth and inhibit cell death [11]. This pathway is involved in regulating autophagy, the ubiquitous and evolutionarily conserved process through which cytosolic components are degraded via lysosomes, helping cells to survive various forms of stress [12]. Recent studies indicate that autophagy and apoptosis are interconnected processes [14]

Methods

Results

Conclusion