Bladder cancer is one of the most frequent cancers among males, and its poor survival rate reflects problems with aggressiveness and chemo-resistance. Recent interest has focused on the use of chemopreventatives (nontoxic natural agents that may suppress cancer progression) to induce targeted apoptosis for cancer therapy. Capsaicin, which has anti-cancer properties, is one such agent. It is known to preferentially inhibit a tumor-associated NADH oxidase (tNOX) that is preferentially expressed in cancer/transformed cells. Here, we set out to elucidate the correlation between tNOX expression and the inhibitory effects of capsaicin in human bladder cancer cells. We showed that capsaicin downregulates tNOX expression and decreases bladder cancer cell growth by enhancing apoptosis. Moreover, capsaicin was found to reduce the expression levels of several proteins involved in cell cycle progression, in association with increases in the cell doubling time and enhanced cell cycle arrest. Capsaicin was also shown to inhibit the activation of ERK, thereby reducing the phosphorylation of paxillin and FAK, which leads to decreased cell migration. Finally, our results indicate that RNA interference-mediated tNOX depletion enhances spontaneous apoptosis, prolongs cell cycle progression, and reduces cell migration and the epithelial-mesenchymal transition. We also observed a downregulation of sirtuin 1 (SIRT1) in these tNOX-knockdown cells, a deacetylase that is important in multiple cellular functions. Taken together, our results indicate that capsaicin inhibits the growth of bladder cancer cells by inhibiting tNOX and SIRT1 and thereby reducing proliferation, attenuating migration, and prolonging cell cycle progression.

Capsaicin (8-methyl-N-vanillyl-6-noneamide), which is an active component in red chili peppers, is used as a chemopreventive agent that shows favorable cytotoxicity against cancer cells. Accumulating evidence indicates that capsaicin preferentially inhibits a tumor-associated NADH oxidase (tNOX, ENOX2) that is ubiquitously expressed in cancer but not in non-transformed cells. This attenuates cancer cell growth by inducing apoptosis. The capsaicin-mediated inhibition of tNOX was recently shown to prolong the cell cycle. However, the molecular events underlying this regulation have not yet been investigated. In the present study, we used a cellular thermal shift assay (CETSA) to detect “target engagement” of capsaicin and its consequent impact on cell cycle progression. Our results indicated that capsaicin engaged with tNOX and triggered the proteasomal degradation of tNOX, which leads to the inhibition of NAD⁺-dependent SIRT1 deacetylase. Ultimately, the acetylation levels of c-Myc and p53 were enhanced, which suppressed the activation of G1 cyclin/Cyclin-dependent kinase complexes and triggered cell cycle arrest in cancer cells. The results obtained when tNOX was overexpressed in non-cancer cells validated its importance in cell cycle progression. These findings provide the first molecular insights into the regulatory role of tNOX and the anti-proliferative property of capsaicin in regulating the cell cycle of bladder cancer cells.

The preoperative prostate-specific antigen (PSA), and the biopsy Gleason score to improve the diagnostic accuracy of prostate cancer (PCa) with organ-confined disease (OCD) or extracapsular extension (ECE)/seminal vesicle invasion (SVI). Methods: Between 2001 and 2007, 94 PCa patients received eMRI testing during presurgical evaluation and underwent radical prostatectomy. As a part of routine patient workup, serum PSA level and Gleason score after pathology examination were recorded. The eMRI images were used to help assess patient PCa staging status regarding OCD or ECE/SVI. These stage assessments as evaluated through the use of MRI were compared with the final specimen pathological stage after the patients underwent radical prostatectomy. Results: Of the total 94 patients in our study, 65 had stage pT2, 12 had stage pT3a, and 17 had stage pT3b PCa. In patients with clinical stage T2 PCa, the Gleason score significantly improved the discriminative ability of eMRI to successfully predict PCa at the OCD stage. Otherwise, in cases of clinical stage T3 PCa, accurate determination of PSA levels significantly improved eMRI predictive ability to assess ECE or SVI staging. Conclusion: In clinical stage T2 PCa patients, integrating the biopsy Gleason score improved the discriminative ability to assess OCD PCa staging. Additionally, combining the preoperative PSA levels of clinical T3 prostate cancer cases with Gleason scores significantly improved the sensitivity and accuracy of eMRI diagnosis to distinguish ECE from SVI....