Abstract
Many tumors constitutively express high levels of the inducible form of proinflammatory enzyme, cyclooxygenase-2 (COX-2). Increased COX-2 expression is associated with tumor cell resistance to many cytotoxic chemotherapy drugs. Furthermore, increased resistance to cytotoxic antitumor drugs is also known to be dependent on associated stromal cells in many tumors. We investigated whether prostate tumor-associated stromal cells, marrow-derived osteoblasts, affect cytotoxicity of 2 antitumor drugs, COL-3 and docetaxel (TXTR), and whether it is dependent on COX-2 activity. We further examined whether inhibiting the activity of COX-2 negate the stroma-induced decrease in drug sensitivity in tumor cells. COX-2-specific inhibitor celecoxib (CXB) was used to inhibit COX-2 activity and associated alteration in cell death signaling was investigated. Coculturing PC-3ML cells with osteoblasts decreased the cytotoxicity of the tested antitumor drugs and was associated with increased COX-2 activity in PC-3ML cells. A significant decrease in drug-induced PGE(2) increase and an increase in cytotoxicity were observed when cells were treated with COL-3 or TXTR combined with CXB. Cytotoxicity of single or combination treatment increased apoptosis, which was associated with caspase-3 and -9 activation, PARP cleavage, increased BAD protein, but decreased protein levels of XIAP and BCL-(xL). Oral administration of CXB (40 mg/kg) to mice with PC-3ML tumors for 42 days increased tumor latency, decreased tumor growth and enhanced tumor control with COL-3 or TXTR. Overall, a synergistic enhancement of antitumor activity in combination treatment was observed in vitro and an additive effect in vivo. These observations suggest a potential clinical use of combined dosing of COX-2 inhibitors and cytotoxic drugs at lower, nontoxic dose than currently used to treat advanced prostate cancer.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects*
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Bone Marrow / drug effects
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Bone Marrow / metabolism
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Carrier Proteins / metabolism
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Caspase 3
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Caspase 9
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Caspases / metabolism*
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Celecoxib
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Cell Cycle / drug effects
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology*
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Dinoprostone / metabolism
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Docetaxel
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Drug Therapy, Combination
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Enzyme Activation / drug effects*
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Gene Expression Regulation, Enzymologic
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Humans
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Male
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Membrane Proteins
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Mice
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Mice, Nude
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Osteoblasts / cytology
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Osteoblasts / drug effects
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Osteoblasts / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Prostaglandin-Endoperoxide Synthases / chemistry
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / pathology
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Prostatic Neoplasms / prevention & control*
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrazoles / pharmacology*
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Stromal Cells / cytology
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Stromal Cells / drug effects
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Stromal Cells / metabolism
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Sulfonamides / pharmacology*
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Taxoids / pharmacology
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Tumor Cells, Cultured
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X-Linked Inhibitor of Apoptosis Protein
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Xenograft Model Antitumor Assays
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bcl-Associated Death Protein
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bcl-X Protein
Substances
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Antineoplastic Agents, Phytogenic
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BAD protein, human
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BCL2L1 protein, human
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Bad protein, mouse
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Bcl2l1 protein, mouse
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Carrier Proteins
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Membrane Proteins
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrazoles
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Sulfonamides
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Taxoids
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-Associated Death Protein
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bcl-X Protein
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Docetaxel
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Poly(ADP-ribose) Polymerases
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CASP3 protein, human
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CASP9 protein, human
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Casp3 protein, mouse
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Casp9 protein, mouse
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Caspase 3
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Caspase 9
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Caspases
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Celecoxib
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Dinoprostone