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Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo
Author(s) -
Abedinpour Parisa,
Baron Véronique T.,
Welsh John,
Borgström Per
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21297
Subject(s) - prostate cancer , medicine , celecoxib , angiogenesis , androgen , prostate , hormonal therapy , tramp , endocrinology , cancer research , androgen deprivation therapy , cancer , oncology , urology , hormone
BACKGROUND Hormonal ablation is the standard of treatment for advanced androgen‐dependent prostate cancer. Although tumor regression is usually achieved at first, the cancer inevitably evolves toward androgen‐independence, in part because of the development of mechanisms of resistance and in part because at the tissue level androgen withdrawal is not fully attained. Current research efforts are focused on new therapeutic strategies that will increase the effectiveness of androgen withdrawal and delay recurrence. We used a syngeneic pseudo‐orthotropic mouse model of prostate cancer to test the efficacy of combining androgen withdrawal with FDA‐approved COX‐2 inhibitor celecoxib. METHODS GFP‐tagged TRAMP‐C2 cells were co‐implanted with prostate tissue in the dorsal chamber model and tumors were allowed to establish and vascularize. Tumor growth and angiogenesis were monitored in real‐time using fluorescent intravital microscopy (IVM). Androgen withdrawal in mice was achieved using surgical castration or chemical hormonal ablation, alone or in combination with celecoxib (15 mg/kg, twice daily). RESULTS Celecoxib alone decreased the growth of prostate tumors mostly by inducing mitotic failure, which resulted in increased apoptosis. Surprisingly, celecoxib did not possess significant angiostatic activity. Surgical or chemical castration prevented the growth of prostate tumors and this, on the other hand, was associated with disruption of the tumor vasculature. Finally, androgen withdrawal combined with celecoxib caused tumor regression through decreased angiogenesis and increased mitosis arrest and apoptosis. CONCLUSION Celecoxib, a relatively safe COX‐2‐selective anti‐inflammatory drug, significantly increases the efficacy of androgen withdrawal in vivo and warrants further investigation as a complement therapy for advanced prostate cancer. Prostate 71:813–823, 2011. © 2010 Wiley‐Liss, Inc.