Background: Although bladder cancer is the second-leading urologic cancer next to prostate cancer in the United States, few effective and satisfactory therapeutic options have yet been established. As we have been searching for certain natural remedies with anticancer activity, we came across the two natural products, namely mushroom extract (PL) and grapeseed extract (GSP). Accordingly, we investigated if the combination of these two extracts could further potentiate anticancer effect on bladder cancer cells. Materials and Methods: Human bladder cancer T24 cells were separately treated with PL, GSP, or their combination, and cell viability was determined by MTT assay. To explore the anticancer mechanism, severity of oxidative stress was assessed by lipid peroxidation (LPO) assay, activities of epigenetic regulators were determined by enzymatic assays, and apoptotic regulators were examined by Western blot analysis. Results: PL and GSP alone led to a ~20% and ~25% cell viability reduction at 20 μg/ml and 25 μg/ml, respectively. When the same concentrations of PL and GSP were then combined, cell viability was drastically reduced to merely ~15% ~85% reduction) in a synergistic manner. Concomitantly, the PL/GSP combination led to a ~3-fold increase in oxidative stress, assessed by LPO assay. Activities of DNA methyltransferase and histone deacetylase were significantly lost by ~50% and 55% with the PL/GSP combination, respectively. Moreover, Western blot analysis revealed that bcl-2 (anti-apoptotic regulator) was down-regulated while Bax (pro-apoptotic regulator) was up-regulated with the combination, implying induction of apoptosis. Conclusions: This study shows that the combination of PL and GSP can synergistically induce the significant reduction (~85%) in T24 cell viability, demonstrating an extensive potentiation of anticancer effect. Such a profound effect is accompanied by increased oxidative stress, chromatin modifications, and ultimate apoptosis. Therefore, the PL/GSP combination may offer a more effective and safer regimen for bladder cancer.

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