Capsaicin is the major pungent ingredient in red peppers. Here, we report that it has a profound antiproliferative effect on prostate cancer cells, inducing the apoptosis of both androgen receptor (AR)-positive (LNCaP) and -negative (PC-3, DU-145) prostate cancer cell lines associated with an increase of p53, p21, and Bax. Capsaicin down-regulated the expression of not only prostate-specific antigen (PSA) but also AR. Promoter assays showed that capsaicin inhibited the ability of dihydrotestosterone to activate the PSA promoter/enhancer even in the presence of exogenous AR in LNCaP cells, suggesting that capsaicin inhibited the transcription of PSA not only via down-regulation of expression of AR, but also by a direct inhibitory effect on PSA transcription. Capsaicin inhibited NF-κ activation by preventing its nuclear migration. In further studies, capsaicin inhibited tumor necrosis factor-α–stimulated degradation of IκBα in PC-3 cells, which was associated with the inhibition of proteasome activity. Taken together, capsaicin inhibits proteasome activity which suppressed the degradation of IκBα, preventing the activation of NF-κB. Capsaicin, when given orally, significantly slowed the growth of PC-3 prostate cancer xenografts as measured by size [75 ± 35 versus 336 ± 123 mm3 (±SD); P = 0.017] and weight [203 ± 41 versus 373 ± 52 mg (±SD); P = 0.0006; capsaicin-treated versus vehicle-treated mice, respectively]. In summary, our data suggests that capsaicin, or a related analogue, may have a role in the management of prostate cancer. (Cancer Res 2006; 66(6): 3222-9)
Prostate cancer is an increasingly prevalent health problem in the U.S., with >230,000 new cases and 29,000 deaths occurring as a result of the disease every year, thereby, constituting the most common male malignancy. Despite the prevalence of the disease, no successful, long-term therapies exist once the cancer has relapsed. The limited therapeutic options provide a strong stimulus for developing new therapeutic approaches.
Capsaicin, a homovanillic acid derivative (8-methyl-N-vanillyl-6-nonenamide), is an active component of the red pepper, genus Capsicum, used for many years in food additives and drugs (1). Topically, capsaicin has therapeutic value in a variety of neuropathic pain conditions including rheumatoid arthritis, cluster headaches, herpes zoster, and vasomotor rhinitis ( 2– 5). Furthermore, capsaicin decreases the growth of human leukemic cells ( 6– 8), gastric ( 9), and hepatic carcinoma cells in vitro ( 10). However, the mechanism of capsaicin-induced growth inhibition remains unclear, and the effect of capsaicin on the growth of human prostate cancer cells has not been studied.
Analysis of androgen-responsiveness of prostate cancer cells often uses prostate-specific antigen (PSA) as a surrogate marker. The 5′ upstream promoter and enhancer region of the PSA gene has several androgen response (AR) elements (ARE), and the expression of PSA is regulated by binding of the liganded AR to these AREs ( 11– 13). A recent study revealed that the nuclear transcription factor κB (NF-κB) is constitutively activated in the androgen-independent prostate cancer cell lines PC-3 and DU-145, but not in the androgen-responsive LNCaP human prostate cancer cells ( 13). NF-κB is a generic term for a dimeric transcription factor formed by heterodimerization or homodimerization of a number of Rel family members ( 14). These transcription factors are activated by a wide range of stimuli, including DNA damage, free radicals, and cytokines, such as tumor necrosis factor-α (TNF-α; ref. 15). In unstimulated cells, NF-κB is maintained in an inactive state in the cytoplasm by complexing with members of the IκB inhibitory protein family, including IκBα and IκBβ ( 16). The interaction between NF-κB and IκBα prevents NF-κB’s nuclear localization and DNA binding activity ( 15, 16). With activation, IκBα kinase (IKK) stimulates the ubiquitination of IκBα, resulting in its degradation by the 26S proteasome complex (17). NF-κB is then free to translocate to the nucleus and act as a transcription factor for a variety of genes, including cytokines, cell cycle regulatory proteins as well as antiapoptotic proteins ( 15, 16, 18). An earlier study noted that capsaicin may exert its anti-growth effects in human myeloid cells through inhibition of the activity of the transcription factor NF-κB by blocking the degradation of IκBα, thereby inhibiting the translocation of the p65 subunit of NF-κB to the nucleus ( 19).
In the present studies, we show that capsaicin has a profound inhibiting effect on the growth of prostate cancer cells in vitro and in vivo, inducing the apoptosis of both AR-positive and AR-negative prostate cancer cell lines. We also showed that capsaicin profoundly decreased the transcription of AR target genes.