Chemopreventive effects of Ganoderma lucidum on human uroepithelial cell carcinoma

Abstract

Background: Superficial transitional cell carcinoma (TCC) is the most common form of bladder cancer that can be managed by the transurethral resection (TUR) technique. TCC faces a challenge of exceptionally high recurrence rate, whereby Bacillus Calmette-Guerin (BCG) is used an adjuvant for prophylaxis. As the most effective immunotherapeutic agent, actions of BCG are based on its internalization by urothelium in order to trigger host immune response. However, the efficacy is unsatisfactory and side effects appear in over 90% of the patients, therefore a more powerful but also a safe chemopreventive agent is demanded. Methodology: An in vitro tumorigenic transferable human uroepithelial cell (HUC-PC) model with carcinogen 4-aminobiphenyl (ABP) was used to evaluate and elucidate the chemopreventive activities of two Ganoderma lucidum extracts - ethanol extract (GLe) and water extract (GLw) for the immunological, oxidative and antioxidant, apoptotic, molecular and cell signaling mechanisms. Results and Discussion: Potent cytotoxic and growth inhibitory effects of GLe were demonstrated as compared to GLw. Surprisingly, GLe induced oxidative stress and oxidative DNA damage in HUC-PC cell line, even though both G. lucidum extracts were found to possess rich antioxidant capacities. GLe was also able to induce interleukin-6 (IL-6) cytokine production, which is also an hallmark of BCG internalization. By using normal HUC-1 cells as control, cytotoxicity of GLe was selective to HUC-PC cells, in particular under ABP challenge. These findings have drawn our attention to demonstrate that the growth inhibition activity of GLe is mainly through (1) telomerase-related apoptosis and (2) up-regulation of intracellular calcium (Ca2+) together with nuclear factor-Kappa B (NF-KB) and protein kinase C (PKC). Furthermore, G. lucidum was capable of modulating the free fibronectin (FN) content as well as the membrane-bound glycosaminoglycans (GAGs) of HUC-PC cells, which may be synergistic to BCG binding efficiency. Conclusion: Conclusive findings support G. lucidum as a novel chemopreventive agent for TCC, whereby it may supplement with BCG for better outcome or potentially substitute BCG when more in vivo evidences become available.