Monoterpenes in Cancer Prevention and Therapy

单萜在癌症预防和治疗中的作用

• 批准号: 6878707
• 负责人: Timothy Scott Vincent
• 金额: $ 7.3万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878707
• 关键词: biomarker; cancer prevention; cell line; chemical conjugate; chemoprevention; chemosensitizing agent; chlorambucil; cisplatin; combination chemotherapy; cytotoxicity; drug resistance; drug screening /evaluation; enzyme activity; gene expression; glutathione; glutathione transferase; monoterpenes; neoplasm /cancer chemotherapy; pharmacokinetics; transcription factor

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.

描述(由申请人提供)： 单萜类化合物是一类具有预防和治疗癌症作用的植物化学物质。典型的单萜紫苏醇(POH)目前正在进行治疗癌症的临床试验。尽管单萜有望作为抗癌剂，但对其作用机制的缺乏阻碍了它们在癌症预防和控制方面的发展。我们最近发现转录调控因子GADD153是单萜作用的潜在生物标志物。GADD153被认为可以控制某些类型的细胞应激反应中的生长停滞和细胞凋亡。预计监测GADD153的表达将使单萜活性的快速和定量评估成为可能。我们还确定了谷胱甘肽(GSH)途径是单萜的分子靶标。观察到GSH水平的下降量与不同单萜抑制生长的效力(ID50)之间有很强的相关性(r值约0.9)，表明这两个事件是联系在一起的。具体目标1将确定GADD153是否是单萜作用的有用标记物，用于区分正常细胞和不同类型的肿瘤细胞的细胞敏感性。特效目标2将确定单萜消耗谷胱甘肽的机制(S)。具体目标3将研究单萜耗尽细胞内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途径而对耐药敏感的药物。 通过了解单萜的作用机制并拥有其活性的有用标记物，应该有可能定义更有效的单萜用于癌症预防和治疗，监测治疗反应，确定哪些类型的癌症可能对单萜治疗更敏感，并确定哪些化疗药物可以通过单萜辅助治疗而得到加强。