Monoterpenes in Cancer Prevention and Therapy

描述（由申请人提供）： 单萜是一类具有癌症预防和治疗特性的植物化学物质。典型的单萜紫苏醇（POH）目前正在临床试验中用于治疗癌症。尽管单萜类化合物有希望作为抗癌剂，但对其作用机制缺乏了解阻碍了其在癌症预防和控制中的发展。我们最近确定了转录调节因子GADD 153作为单萜作用的潜在生物标志物。GADD 153被认为控制响应于某些类型的细胞应激的生长停滞和凋亡。预计监测GADD 153表达将允许快速和定量评估单萜活性。我们还确定了谷胱甘肽（GSH）途径作为单萜的分子靶点。观察到GSH水平降低量与各种单萜的生长抑制效力（ID 50）之间存在强相关性（r值约为0.9），表明这两个事件相关。特异性目的1将确定GADD 153是否是用于正常细胞和各种肿瘤细胞类型之间的差异细胞敏感性的单萜作用的有用标志物。具体目标2将确定单萜消耗GSH的机制。具体目标3将检查单萜类消耗细胞GSH将使肿瘤细胞对化疗敏感的可能性，特别强调通过调节GSH途径对耐药敏感的药物。 通过了解单萜类的作用机制并具有其活性的有用标志物，应该可以定义用于癌症预防和治疗的更有效的单萜类，监测治疗反应性，确定哪种类型的癌症可能对单萜治疗更敏感，并鉴定哪种化疗剂可以通过单萜辅助治疗来增强。

DESCRIPTION (provided by applicant): Monoterpenes are a class of phytochemicals that possess cancer preventative and therapeutic properties. The prototypical monoterpene Perillyl alcohol (POH) is currently in clinical trials for the treatment of cancers. In spite of their promise of monoterpenes as anticancer agents, a lack of understanding of their mechanism of action has hampered their development in cancer prevention and control. We recently identified the transcriptional regulator, GADD153, as a potential biomarker for monoterpene action. GADD153 is thought to control growth arrest and apoptosis in response to certain types of cellular stress. It is anticipated that monitoring GADD153 expression will allow rapid and quantitative assessment of monoterpene activity. We have also identified the glutathione (GSH) pathway as the molecular target of monoterpenes. A strong correlation (r-value approximately 0.9) was observed between amount of decrease in GSH levels and the potency (ID50) for growth suppression by a various monoterpenes indicating that these two events are linked. Specific Aim 1 will determine whether GADD153 is a useful marker of monoterpene action for differential cell sensitivity between normal cells and various tumor cell types. Specific Aim 2 will determine the mechanism(s) by which monoterpenes deplete GSH. Specific Aim 3 will examine the possibility that depletion of cellular GSH by monoterpenes will sensitize tumor cells to chemotherapy with particular emphasis place on agents that are susceptible to resistance through modulation of the GSH pathways. By understanding the mechanism of action of monoterpenes and having a useful marker of its activity it should be possible to define more effective monoterpenes for cancer prevention and therapy, monitor therapeutic responsiveness, determine which types of cancer might be more responsive to monoterpene therapy, and identify which chemotherapeutic agents may be augmented by monoterpene adjuvant therapy.