alexa SF1126, a Pan-PI3K Inhibitor has Potent Pre-Clinical Activity in Aggressive B-Cell Non-Hodgkin Lymphomas by Inducing Cell Cycle Arrest and Apoptosis
ISSN: 1948-5956

Journal of Cancer Science & Therapy
Open Access

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Research Article

SF1126, a Pan-PI3K Inhibitor has Potent Pre-Clinical Activity in Aggressive B-Cell Non-Hodgkin Lymphomas by Inducing Cell Cycle Arrest and Apoptosis

Wenqing Qi1*, Amy Stejskal1, Carla Morales1, Laurence S. Cooke1, Joseph R. Garlich1,2 and Daruka Mahadevan1*

1Arizona Cancer Center, Tucson, AZ85724, USA

2Semafore Pharmaceuticals, Indianapolis, Indiana, USA

*Corresponding Author:
Daruka Mahadevan
Arizona Cancer Center, 1515
N Campbell Avenue
Tucson, AZ85724, USA
Tel: (520) 626-4331
Fax: (520) 626- 2225
E-mail: [email protected]
Wenqing Qi
Arizona Cancer Center
1515 N Campbell Avenue
Tucson, AZ85724, USA
Tel: (520) 626-0190
Fax: (520) 626-2225
E-mail: [email protected], [email protected]

Received Date: June 11, 2012; Accepted Date: July 19, 2012; Published Date: July 21, 2012

Citation: Qi W, Stejskal A, Morales C, Cooke LS, Garlich JR, et al. (2012) SF1126, a Pan-PI3K Inhibitor has Potent Pre-Clinical Activity in Aggressive B-Cell Non- Hodgkin Lymphomas by Inducing Cell Cycle Arrest and Apoptosis. J Cancer Sci Ther 4: 207-213 doi:10.4172/1948-5956.1000143

Copyright: © 2012 Qi W, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

Abstract

The PI3K pathway is activated in a variety of human tumors including B-cell Non Hodgkin Lymphoma (B-NHL). Targeting this pathway has been validated in solid tumors, leukemia and lymphomas. SF1126, a novel pan-PI3K inhibitor designed by conjugating RGD peptide to LY294002 facilitates clinical testing of this prodrug, suppresses growth and survival of multiple solid tumors in vitro and in vivo. In this study, we demonstrated SF1126 had potent activity in a panel of aggressive B-NHL cell lines. Cells treated with SF1126 exhibited decreased phosphorylation of Akt and GSK-3β confirming the mechanism of action of a PI3K inhibitor. Also, treatment of B-NHL cell lines with SF1126 induced apoptosis in a dose-dependent manner and inhibited cell proliferation with an IC50 < 4 μM. However, the selective p110δ inhibitor, CAL-101 was less potent in inducing apoptosis and inhibiting cell proliferation compared to SF1126. Moreover, SF1126 induced G1 cell cycle arrest significantly at low concentrations which contributed to suppression of cell proliferation and corroborated to a decrease in cyclin D1. Finally, rituximab enhanced apoptosis induced by SF1126 and CAL-101. Taken together, our findings provide for the first time that SF1126 inhibits the constitutively activated PI3K/Akt pathway in aggressive B-cell NHL cell lines with associated inhibition of cell cycle progression, cell proliferation and promotion of apoptosis. These findings suggest that SF1126 is a novel therapeutic strategy in aggressive B-cell NHL and warrants early phase clinical trial evaluation ± rituximab.

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