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 Farag

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

Fingerprint

Celecoxib
Multiple Myeloma
STAT3 Transcription Factor
Apoptosis
Caspases
Cell Death
OSU 03012
Janus Kinase 2
G2 Phase Cell Cycle Checkpoints
70-kDa Ribosomal Protein S6 Kinases
Cyclin B
Glycogen Synthase Kinase 3
Cyclin A
1-Phosphatidylinositol 4-Kinase
Caspase 9
Caspase 8

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms. / Zhang, Shuhong; Suvannasankha, Attaya; Crean, Colin D.; White, Valerie L.; Johnson, Amy; Chen, Ching Shih; Farag, Sherif.

In: Clinical Cancer Research, Vol. 13, No. 16, 15.08.2007, p. 4750-4758.

Research output: Contribution to journalArticle

Zhang, Shuhong ; Suvannasankha, Attaya ; Crean, Colin D. ; White, Valerie L. ; Johnson, Amy ; Chen, Ching Shih ; Farag, Sherif. / OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 16. pp. 4750-4758.
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T1 - OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms

AU - Zhang, Shuhong

AU - Suvannasankha, Attaya

AU - Crean, Colin D.

AU - White, Valerie L.

AU - Johnson, Amy

AU - Chen, Ching Shih

AU - Farag, Sherif

PY - 2007/8/15

Y1 - 2007/8/15

N2 - 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.

AB - 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.

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