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Pro-apoptotic activity of ergosterol derivatives in human prostate cancer cells
Steroids are abundantly present in mushrooms and were reported to have diverse biological activities, such as anti-oxidant effects, anti-inflammatory activity and inhibitory effects on cancer cell growth . In particular, ergosterol peroxide (5α,8α-epidioxy-22E-ergosta-6, 22-dien-3β-ol) inhibits the growth of some cancer cells and induces apoptosis of human leukaemia cells [1–3]. Apoptosis is suggested as one of the major mechanisms for the targeted therapy of prostate cancer . With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on prostate cancer cells, we assayed the effect of two derivatives of ergosterol (ergosta-5,7,22-trien-3β-ol), ergosterol acetate and (22E)-ergosta-7,22-dien-5α-hydroxy-3,6-dione against androgen-sensitive (LNCaP) and androgen-insensitive (DU-145) human prostate cancer cells. Our results indicate that after 72h of incubation ergosterol derivatives exhibited a inhibitory effect on LNCaP and DU-145 cell growth (MTT assay). Ergosterol acetate and (22E)-ergosta-7,22-dien-5α-hydroxy-3,6-dione were significantly (p<0.001) more active than ergosterol peroxide, with IC50 value in LNCaP cells of 8.44 and 6.37µM, respectively, and in DU-145 cells of 7.46 and 6.12µM, respectively. In addition, our results indicate that apoptotic cell demise is induced in LNCaP and DU-145 cells. In fact, a significant increase (p<0.01–0.001) of caspase-3 activity, no correlated to LDH release, marker of membrane breakdown, was observed in both cell lines treated with ergosterol derivatives at all the doses (6.25–50µM). With respect to genomic DNA damage, determined by COMET assay, the results obtained show a significant (p<0.001) increase of TDNA and TMOM values when compared with the untreated control.
References: 1. Kobori, M. et al. (2006) Biol. Pharm. Bull. 29:755–759.
2. Takei, T. et al. (2005) Biosci. Biotechnol. Biochem. 69:212–215.
3. Kobori, M. et al. (2007) Br. J. Pharmacol. 150:209–219.
4. Lowe, S.W., Lin, A.W. (2000) Carcinogenesis 21: 485–495.