Prostate cancer (PCa) is common and a frequent cause of cancer death among men worldwide. Moreover, PCa rates have risen quite significantly in the last decade in Singapore men and although some of the increase can be attributed to enhanced detection, much of the increased incidence is associated with genetic alterations and life-style related factors. Current therapies for metastatic prostate cancer are only marginally effective, and hence new treatment modalities are urgently needed. Considerable evidence suggests that chronic inflammation plays a pivotal role in the development and progression of PCa. Thus, the agents that can suppress inflammatory mediators have a potential in treatment of PCa. One way to expedite drug development is to find new uses for drugs already in clinical use. Hence we propose to investigate the role of artesunate, (a drug approved for the treatment of multidrug-resistant malaria) in PCa using diverse prostate cancer cell lines. In this study, we investigated the effect of artesunate (ART) primarily on signal transducer and activator of transcription 3(STAT3) signaling pathway in both androgen independent (DU145) and androgen dependent (LNCaP) PCa cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that ART inhibited constitutive and IL-6-induced activation of STAT3 in DU145 and LNCaP cells in a dose and time dependent manner. We observed that STAT3 suppression by ART was mediated through the inhibition of activation of upstream kinases such as (c-Src, JAK1, and JAK2) and generation of reactive oxygen species (ROS) was also involved in this process. Our preliminary findings further indicate that ART also suppressed constitutive NF-κB activation in PCa cells. ART exhibited significant anti-proliferative effects and abrogated the migratory/invasive potential of PCa cells. Moreover, ART down-regulated the expression of various NF-κB and STAT3 regulated gene products involved in proliferation, survival and angiogenesis, also induced apoptosis in PCa cells lines as evident by DNA fragmentation and Annexin V staining. Overall our preliminary results from experimental and predictive studies indicate that ART mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in PCa.
Citation Format: Alamelu Nachiyappan, Muthu K Shanmugam, Feng Li, Alan Prem Kumar, Gautam Sethi. Artesunate inhibits multiple proinflammatory transcription factors leading to the suppression of growth and induction of apoptosis in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3790. doi:10.1158/1538-7445.AM2014-3790