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OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms

Authors' Affiliations: ¹ Division of Hematology and Oncology, Department of Internal Medicine, and ² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; and ³ Division of Hematology and Oncology, Department of Internal Medicine, and ⁴ Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio

Requests for reprints: Sherif S. Farag, Departments of Medicine and Medical and Molecular Genetics, Indiana University School of Medicine, 635 Barnhill Drive, Room 224G, Indianapolis, IN 46202. E-mail: ssfarag{at}iupui.edu.

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-3ß, 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 down-regulated, 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.

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