The combined treatment of 1,25-dihydroxyvitamin D3 and a non-steroid anti-inflammatory drug is highly effective in suppressing prostate cancer cell line (LNCaP) growth.
BACKGROUND
The active metabolite of vitamin D3, 1,25(OH)2D3, is known to possess anti-proliferative and pro-differentiative activities in prostate cancer (PCa) cells. However, its clinical use is limited because of the risk of hypercalcemia. Concurrent administration of lower doses of 1,25(OH)2D3 together with other anticancer drugs may help to overcome this obstacle and lead to an effective and tolerable therapy. In the present in vitro study, we investigated the combined anti-cancer effect of 1,25(OH)2D3 and ibuprofen, a well-known non-steroidal anti-inflammatory drug (NSAID) that is also recognized for its ability to reduce prostate cancer development.


METHODS
An androgen-sensitive prostate cancer cell line (LNCaP), grown in medium containing androgen (5alpha-dihydrotestosterone (DHT)) or without it, was treated with 1,25(OH)2D3 or ibuprofen alone or with a combination of both drugs. The effects of the treatments on LNCaP cell proliferation, cell cycle and apoptosis were evaluated by the thymidine incorporation method, the propidium iodide method and ELISA, respectively. The unpaired t-test was used for statistical analysis.


RESULTS
Simultaneous treatment of LNCaP cells grown without DHT with 10 nM 1,25(OH)2D3 and 0.2 mM ibuprofen decreased cell growth by 42% (p<0.001, compared to the control cells). This effect was found to be additive since each single drug reduced cell proliferation by only 24%. On the other hand, highly significant synergistic cell growth inhibition (67%, p<0.001) was achieved by combined treatment of 1,25(OH)2D3 and ibuprofen in DHT-stimulated LNCaP cells. This combined treatment was also found to be effective in decreasing the cell transition from G1- to S-phase (p<0.003) and effective in enhancing apoptosis.


CONCLUSIONS
Although both 1,25(OH)2D3 and ibuprofen demonstrate in vitro anti-carcinogenic activities as a single drug treatment, the present results showed that the combined use of 1,25(OH)2D3 with ibuprofen is superior to treatment with a single drug.
Gavrilov
Vladimir
V
Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev and Soroka Medical Center, Beer-Sheva 84105, Israel.
Steiner
Michael
M
Shany
Shraga
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D013196:Dihydrotestosterone; D002117:Calcitriol; D007052:Ibuprofen