OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms

Shuhong Zhang, Attaya Suvannasankha, Colin D. Crean, Valerie L. White, Amy Johnson, Ching Shih Chen, Sherif S. Farag

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45 Scopus citations

Abstract

Purpose: OSU-03012 is a novel celecoxib derivative, without cyclooxygenase-2 inhibitory activity, capable of inducing apoptosis in various cancer cells types, and is being developed as an anticancer drug. We investigated the in vitro activity of OSU-03012 in multiple myeloma (MM) cells. Experimental Design: U266, ARH-77, IM-9, and RPMI-8226, and primary myeloma cells were exposed to OSU-03012 for 6, 24, or 72 h. Cytotoxicity, caspase activation, apoptosis, and effects on intracellular signaling pathways were assessed. Results: OSU-03012 was cytotoxic to MM cells with mean LC50 3.69 ± 0.23 and 6.25 ± 0.86 μmol/L and at 24 h for primary MM cells and cell lines, respectively. As a known PDK-1 inhibitor, OSU-03012 inhibited the PI3K/Akt pathway with downstream effects on BAD, GSK-3β, FoxO1a, p70S6K, and MDM-2. However, transfection of MM cells with constitutively active Akt failed to protect against cell death, indicating activity against other pathways is important. Phospho (p)-signal transducers and activators of transcription 3 and p-MAP/ERK kinase 1/2 were downregulated, suggesting that OSU-03012 also inhibited the Janus-activated kinase 2/signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways. Although expression of Bcl-2 proteins was unchanged, OSU-03012 also down-regulated survivin and X-linked inhibitor of apoptosis (XIAP), and also induced G2 cell cycle arrest with associated reductions in cyclins A and B. Finally, although OSU-03012 induced cleavage of caspases 3, 8 and 9, caspase inhibition did not prevent cell death. Conclusions: We conclude that OSU-03012 has potent activity against MM cells and acts via different mechanisms in addition to phosphoinositide-3-kinase/Akt pathway inhibition. These studies provide rationale for the clinical investigation of OSU-03012 in MM.

Original languageEnglish (US)
Pages (from-to)4750-4758
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number16
DOIs
StatePublished - Aug 15 2007

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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