Induction of inflammatory cytokines and alteration of urothelial ATP, acetylcholine and prostaglandin E2 release by doxorubicin

Sung Hyun Kang, Russ Chess-Williams, Shailendra Anoopkumar-Dukie, Catherine McDermott

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Abstract

Intravesical treatment with cytotoxic drugs such as doxorubicin is associated with local adverse effects in bladder cancer patients. Here we investigate the effects of doxorubicin on urothelial release of ATP, acetylcholine and prostaglandin E2, and production of inflammatory cytokines. Urothelial cells were treated with doxorubicin for 1 h at 37 °C. Immediately or 24 h following treatment the level of ATP, acetylcholine and prostaglandin E2 released under basal and stimulated conditions was measured and compared to release from vehicle treated control cultures. The presence of inflammatory cytokines, in culture medium was also assessed 24 h after doxorubicin pre-treatment. Immediately following treatment, stimulated ATP release was inhibited at doxorubicin concentrations ≥1 μg/ml and showed partial recovery at 24 h. Immediately following treatment, basal acetylcholine release was increased by doxorubicin at its clinical concentration (1 mg/ml), while a concentration-dependent decrease in stimulated acetylcholine release was observed. Twenty four hour after treatment, basal acetylcholine release was increased in culture treated with 0.01 mg/ml doxorubicin while stimulated acetylcholine release remained depressed. A significant increase in prostaglandin E2 release was observed in cells immediately and 24 h after treatment with doxorubicin. A 5.5- and 2-fold increase in interleukin -8 and -1β secretion, respectively was detected 24 h following doxorubicin treatment. These findings indicate that inflammatory cytokines interleukin-8 and -1β are induced and urothelial mediator release is affected by treatment with doxorubicin at clinically relevant concentrations and durations of treatment. These changes may play a role in the adverse effects associated with intravesical doxorubicin treatment.

Original languageEnglish
Pages (from-to)102-109
Number of pages8
JournalEuropean Journal of Pharmacology
Volume700
Issue number1-3
DOIs
Publication statusPublished - 30 Jan 2013

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Dinoprostone
Doxorubicin
Acetylcholine
Adenosine Triphosphate
Cytokines
Therapeutics
Interleukin-8
Interleukin-1
Urinary Bladder Neoplasms
Culture Media

Cite this

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title = "Induction of inflammatory cytokines and alteration of urothelial ATP, acetylcholine and prostaglandin E2 release by doxorubicin",
abstract = "Intravesical treatment with cytotoxic drugs such as doxorubicin is associated with local adverse effects in bladder cancer patients. Here we investigate the effects of doxorubicin on urothelial release of ATP, acetylcholine and prostaglandin E2, and production of inflammatory cytokines. Urothelial cells were treated with doxorubicin for 1 h at 37 °C. Immediately or 24 h following treatment the level of ATP, acetylcholine and prostaglandin E2 released under basal and stimulated conditions was measured and compared to release from vehicle treated control cultures. The presence of inflammatory cytokines, in culture medium was also assessed 24 h after doxorubicin pre-treatment. Immediately following treatment, stimulated ATP release was inhibited at doxorubicin concentrations ≥1 μg/ml and showed partial recovery at 24 h. Immediately following treatment, basal acetylcholine release was increased by doxorubicin at its clinical concentration (1 mg/ml), while a concentration-dependent decrease in stimulated acetylcholine release was observed. Twenty four hour after treatment, basal acetylcholine release was increased in culture treated with 0.01 mg/ml doxorubicin while stimulated acetylcholine release remained depressed. A significant increase in prostaglandin E2 release was observed in cells immediately and 24 h after treatment with doxorubicin. A 5.5- and 2-fold increase in interleukin -8 and -1β secretion, respectively was detected 24 h following doxorubicin treatment. These findings indicate that inflammatory cytokines interleukin-8 and -1β are induced and urothelial mediator release is affected by treatment with doxorubicin at clinically relevant concentrations and durations of treatment. These changes may play a role in the adverse effects associated with intravesical doxorubicin treatment.",
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Induction of inflammatory cytokines and alteration of urothelial ATP, acetylcholine and prostaglandin E2 release by doxorubicin. / Kang, Sung Hyun; Chess-Williams, Russ; Anoopkumar-Dukie, Shailendra; McDermott, Catherine.

In: European Journal of Pharmacology, Vol. 700, No. 1-3, 30.01.2013, p. 102-109.

Research output: Contribution to journalArticleResearchpeer-review

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