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

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 LC 50 3.69 F 0.23 and 6.25 F 0.86 Amol/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-3h, 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 G 2 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.

Sensitizing estrogen receptor–negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor

“…Second, our data suggest that OSU-03012-mediated Akt inhibition interacted cooperatively with the ER-independent actions of tamoxifen in modulating the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3a/h, and p27. Third, OSU-03012-induced apoptosis in cancer cells has been associated with effects on pathways other than PDK-1/Akt signaling, including the disruption of mitochondrial membrane potential and activation of caspase-9 (5, 9), induction of endoplasmic reticulum stress responses (11), inhibition of p21-activated kinase 1 activity (25), inhibition of Janus-activated kinase 2/signaling transducer activator of transcription 3 and MAPK pathways, and downregulation of cyclins A and B and the inhibitor of apoptosis protein (22) members, X-linked inhibitor of apoptosis, and survivin (26). Thus, these and perhaps other OSU-03012-induced apoptotic pathways may merge with those induced by tamoxifen to culminate in enhanced breast cancer cell death.…”

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

“…Of special interest is OSU-03012, a celecoxib derivative, inducing PCD in a large variety of cancer cells (e.g., multiple myeloma or glioma cells). OSU-03012-mediated death is dependent on ER stress, lysosomal dysfunction, Bid-activation and release of AIF (37,104). The synthetic drug Bobel-24 (2,4,6-triiodophenol) triggers caspase-independent lysosomal and mitochondrial death in human pancreatic cancer lines.…”

OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species–Related Autophagy in Hepatocellular Carcinoma

“…For example, OSU-03012 has been shown to induce apoptosis by activation of the intrinsically mitochondrial pathway in primary chronic lymphocytic leukemia cells (5). OSU-03012 also inhibited c-Jun NH 2 -terminal kinase/ signal transducers and activators of transcription and mitogenactivated protein kinase pathways in multiple myeloma cells (6). Further, OSU-03012 has been reported to cause a PDK1/AKTindependent cell death in glioma cells (7).…”