Abstract 3554: The fungal metabolite galiellalactone inhibits ALDH positive prostate cancer cells
Authors: Rebecka Hellsten, Anna Dahlman, Zoran Culig, Martin Johansson, Olov Sterner, Anders Bjartell
Journal: Cancer Research (2010)

Abstract Introduction: Tumor stem cells have shown resistance to conventional cancer therapy and may be a cause for recurrent cancer, making tumor stem cell targeted therapy attractive. The fungal metabolite galiellalactone is suggested to be a Stat3 specific inhibitor and we have previously shown that galiellalactone inhibits prostate cancer (PCa) cell growth, both in vitro and in vivo, in PCa cells expressing phosphorylated Stat3 (Hellsten et al, 2008). Aldehyde dehydrogenase (ALDH) has shown promise as a marker of cancer stem cells and in this study we investigated the ALDH activity in human PCa cell lines and the effects of galiellalactone on ALDH+ PCa cells. Methods: The human PCa cell lines DU145, LNCaP, and long-term interleukin-6 stimulated LNCaP (LNCaP-IL6) cells were used. Galiellalactone was prepared by synthesis (Johansson &amp; Sterner, 2002). PCa cells were subjected to Aldefluor assay followed by flow cytometry to detect ALDH+ subpopulations. WST-1 proliferation assay was performed to study the effect of galiellalactone on proliferation of ALDH+ and ALDH- cells sorted from LNCaP-IL6 cells. Results: In DU145 cells 2 ± 0.25% of the cells were ALDH+ and in LNCaP-IL6 cells, 2 ± 0.36% were ALDH+. No ALDH+ cells were detected in LNCaP cells. Treatment with 5, 10, 25 or 50 µM galiellalactone for 24h decreased the ALDH+ cell population in DU145 and LNCaP-IL6 cells in a dose dependent manner: 25 µM galiellalactone decreased the ALDH+ population in DU145 cells by 40% and by 75% in LNCaP-IL6 cells. In LNCaP-IL6 cells a dose dependent decrease in ALDH+ cells was observed after 72h (65% decrease at 25 µM galiellalactone). However, in DU145 cells no difference in the relative amount of ALDH+ cells was observed in galiellalactone treated DU145 cells compared to untreated control cells after 72h. The proliferation was decreased by galiellalactone in a dose dependent manner in all cell populations isolated from LNCaP-IL6 cells. The proliferation of ALDH+ cells isolated from LNCaP-IL6 cells was inhibited by 75%, ALDH- cells by 75% and unsorted LNCaP-IL6 cells by 80% after treatment with 25 µM galiellalactone for 48h. Conclusions: ALDH+ subpopulations, possibly representing tumor stem cell populations were detected in human PCa cell lines, and were clearly inhibited by galiellalactone. ALDH is associated with cell growth and drug resistance, and targeting ALDH+ PCa cells with galiellalactone may be a novel potent treatment against therapy resistant PCa. The effect and mechanism of galiellalactone treatment of ALDH+ PCa cells will be further investigated. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3554.