Development of dihydroartemisinin as a novel preventive agent for prostate cancer

描述（由申请人提供）： 双氢青蒿素（DHA）是青蒿素的活性代谢产物。青蒿素是1972年从中药青蒿中首次发现和提取的。DHA已被广泛用于临床治疗疟疾，并且人类和动物耐受性良好。在我们的初步研究中，我们发现DHA诱导人前列腺癌细胞凋亡。我们还发现，DHA上调死亡受体5（DR 5），并与TRAIL（DR 5的配体，可能成为一种新的无毒抗癌剂）合作，诱导人前列腺癌细胞凋亡。此外，DHA强烈抑制Akt（蛋白激酶B），Akt是传导生存信号的关键因素。NKX3.1是一种同源域转录因子，其功能与抑制前列腺癌发生有关。我们的初步结果还表明NKX3.1上调DR 5启动子功能。因此，我们假设抗疟疾药物DHA具有预防前列腺癌的显著潜力。我们的初步结果支持我们的假设，并形成本申请的基础，以进一步研究DHA介导其抗癌作用的分子机制，并开发这种药物作为一种新的前列腺癌的癌症预防剂。我们提出两个具体目标来检验我们的假设。具体目标1是研究同源域NKX3.1转录因子在介导DHA诱导的DR 5上调中的作用。具体目的2是研究DHA在TRAMP和Nkx3.1/Pten突变小鼠中的前列腺癌预防作用。这些都是试点研究，如果成功，将（i）提供重要的见解DHA介导其细胞凋亡和抗癌作用的分子机制和（ii）奠定基础，开发DHA作为一种新的癌症预防剂的前列腺癌。

DESCRIPTION (provided by applicant): 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.