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 Qi, Amy Stejskal, Carla Morales, Laurence S. Cooke, Joseph R. Garlich, Donald Durden, Daruka Mahadevan

Research output: Contribution to journalArticle

4 Scopus citations

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 IC 50 < 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.

Original languageEnglish (US)
Pages (from-to)207-213
Number of pages7
JournalJournal of Cancer Science and Therapy
Volume4
Issue number7
DOIs
StatePublished - Sep 17 2012

    Fingerprint

Keywords

  • Apoptosis
  • B-cell non-Hodgkin lymphoma
  • CAL-101
  • Cell cycle
  • PI3K
  • SF1126

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this