Dihydroartemisinin (DHA) is an active metabolite of artemisinin. Artemisinin was first identified and extracted from traditional Chinese medicine qinghao (plant Artemisia annua L) in 1972. DHA has been extensively used in the clinic to treat malaria and is well-tolerated by humans and animals. In our preliminary studies, we have found that DHA induces apoptosis in human prostate cancer cells. We have also found that DHA upregulates death receptor 5 (DR5) and cooperates with TRAIL (the ligand for DR5 that has potentially emerged as a novel nontoxic anticancer agent) to induce apoptosis in human prostate cancer cells. Furthermore, DHA strongly inhibits Akt (protein kinase B), which is a key player in transducing survival signals. NKX3.1 is a homeodomain transcription factor and its function is linked to inhibition of prostate carcinogenesis. Our preliminary results also indicate that NKX3.1 upregulates DR5 promoter function. Therefore, we hypothesize that the anti-malarial drug DHA has a significant potential for prevention of prostate cancer. Our preliminary results support our hypothesis and form the basis of this application to further study the molecular mechanisms by which DHA mediates its anticancer effect and to develop this agent as a novel cancer-preventive agent for prostate cancer. We are proposing two specific aims to test our hypothesis.
Specific Aim 1 is to investigate the role of homeodomain NKX3.1 transcription factor in mediating DHA-induced upregulation of DR5.
Specific Aim 2 is to investigate the prostate cancer preventive effects of DHA in TRAMP and Nkx3.1/Pten mutant mice. These are pilot studies and if successful, will (i) provide important insights into the molecular mechanisms by which DHA mediates its apoptotic and anticancer effects and (ii) lay the groundwork to develop DHA as a novel cancer-preventive agent for prostate cancer.

Public Health Relevance

Prostate cancer is one of the major human malignancies and a leading cause of deaths in American men. Because prostate cancer is a disease of the elderly there is a long latent period before the disease is detected. Due to the long latent period, prostate cancer is amenable to chemopreventive strategies. Thus, chemoprevention-mediated delay in the development of prostate cancer, even small, is expected to diminish the prostate cancer incidence and improve the quality of life. Newer and more effective therapeutic and preventive strategies are therefore urgently needed to fight against prostate cancer. Dihydroartemisinin (DHA) is an active metabolite of artemisinin, a plant extract. DHA has been extensively used in the clinic to treat malaria and is well-tolerated by humans and animals. In our preliminary studies, we have found that DHA also show anticancer potential in human prostate cancer cells. Therefore, we hypothesize that the anti- malarial drug DHA has a significant potential for prevention of prostate cancer. Our preliminary results support our hypothesis and form the basis of this application to further study the molecular mechanisms by which DHA mediates its anticancer effects and to develop this agent as a novel cancer-preventive agent for prostate cancer. Here we are proposing pilot studies, which, if successful, will lay the groundwork to develop DHA as a novel cancer-preventive agent for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA150132-02
Application #
8242022
Study Section
Special Emphasis Panel (ZCA1-SRLB-F (O1))
Program Officer
Perloff, Marjorie
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$79,750
Indirect Cost
$29,750
Name
Upstate Medical University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210