2. Academic Validation
  3. Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment

Cyclooxygenase-2 inhibition prevents renal toxicity but not hypertension during sunitinib treatment

  • Eur J Pharmacol. 2023 Nov 27:176199. doi: 10.1016/j.ejphar.2023.176199.
Daan C H van Dorst 1,  Katrina M Mirabito Colafella 2,  Richard van Veghel 3,  Ingrid M Garrelds 3,  René de Vries 3,  Ron H J Mathijssen 4,  A H Jan Danser 3,  Jorie Versmissen 5
Affiliations

Affiliations

  • 1 Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. Electronic address: [email protected].
  • 2 Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia.
  • 3 Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • 4 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
  • 5 Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Hospital Pharmacy, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
PMID: 38029870 DOI: 10.1016/j.ejphar.2023.176199
Abstract

Background: Anticancer angiogenesis inhibitors cause hypertension and renal injury. Previously we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and-2) was superior to low-dose aspirin (blocking COX-1 only) to prevent these side-effects during treatment with the angiogenesis inhibitor sunitinib, suggesting a role for COX-2. High-dose aspirin additionally prevented the rise in COX-derived prostacyclin (PGI2). Therefore, we studied the preventive effects of selective COX-2 inhibition and the hypothesized contributing role of PGI2 during angiogenesis inhibition.

Methods: Male WKY rats received vehicle, sunitinib ((SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day) or a PGI2 analogue (iloprost, 100 μg/kg/day) for 8 days (n = 8-9 per group). Mean arterial pressure (MAP) was measured via radiotelemetry, biochemical measurements were performed via ELISA and vascular function was assessed via wire myography.

Results: SU increased MAP (17±1mmHg versus 3±1mmHg after vehicle on day 4, P < 0.002), which could not be significantly blunted by celecoxib (+12±3mmHg on day 4, P = 0.247), but was temporarily attenuated by iloprost (treatment days 1 + 2 only). Urinary PGI2 (996 ± 112 versus 51 ± 11ng/24h after vehicle, P < 0.001), but not circulating PGI2 increased during SU, which remained unaffected by celecoxib and iloprost. Celecoxib reduced sunitinib-induced albuminuria (0.36 ± 0.05 versus 0.58 ± 0.05mg/24h after SU, P = 0.005). Wire myography demonstrated increased vasoconstriction to endothelin-1 after SU (Emax P = 0.005 versus vehicle), which remained unaffected by celecoxib or iloprost.

Conclusion: Selective COX-2 inhibition ameliorates albuminuria during angiogenesis inhibition, which most likely acts independently of PGI2. To combat angiogenesis inhibitor-induced hypertension, dual rather than selective COX-1/2 blockade seems preferential.

Keywords

Angiogenesis inhibitors; Cardio-oncology; Cyclooxygenase-2; Hypertension; Prostanoids; Renal toxicity.

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