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Sesquiterpene Lactones: Aspirins for Breast Cancer
Tumor Cell Biology V
Background: Parthenolide is a sesquiterpene lactone (SQL) and the primary anti-inflammatory agent in the herbal remedy feverfew (Tanacetum parthenium). Feverfew has traditionally been used in the treatment of inflammatory conditions such as headaches, arthritis, and fevers. More recently, parthenolide has been shown to prevent UVB-induced skin cancer, to sensitize breast cancer cells towards TRAIL-induced apoptosis, and to selectively target AML and CML stem cell populations, presumably through a mechanism involving IKK2 activation of NF-kappaB. Our laboratory has been investigating the effects of parthenolide treatment on breast cancer cells. We found that parthenolide treatment caused a rapid and complete depletion of cellular HDM2 levels and a concomitant increase in the cell cycle regulator p53. Parthenolide treatment also caused a significant depletion of histone deacetylase 1, with a resulting upregulation of the important cell cycle regulator p21WAF1/CIP1. Most surprisingly, these effects were not dependent on IKK2 or RelA, suggesting that they were independent of activated NF-kappaB. Objective/Hypothesis: SQLs like parthenolide can be highly effective multifunctional agents for the chemoprevention and treatment of breast cancer. In order to develop this class of molecules, we need to identify the best candidates and understand their mechanisms of action. Specific Aims/Study Design: (1) Examine the effects of different SQLs on the proliferation, viability, apoptosis, and necroptosis of a panel of normal and breast cancer cells using standard assays. (2) Examine above SQL effects in the presence of conventional chemotherapeutics, including ER antagonists, cytotoxics, and trastuzumab. (3) Use small molecule inhibitors and/or siRNAs to probe signal transduction pathways for SQL molecular and cellular effects. (4) Use chemical genetic approaches to identify protein partners of SQLs. Outcomes: (1) Identification of SQL moieties responsible for activity. (2) Identification of breast cell characteristics responsible for SQL sensitivity. (3) Determine synergistic effects between SQLs and conventional therapeutics. (4) Determine mechanisms of SQL action. Relevance: SQLs are relatively non-toxic agents, yet are very effective at many levels against transformed cells. Understanding these molecules and their mechanisms of action will yield a new class of chemopreventatives and/or adjuvants for breast cancer chemotherapy.
Ideally, one would like to prevent or treat breast cancer with as generally non-toxic substances as possible. This would be analogous to the use of aspirin in the prevention of cardiovascular diseases and in the prevention and treatment of colorectal cancers. Aspirin, specifically its active ingredient acetylsalicylic acid, acts at many levels within cells to inhibit processes such as pain and inflammation. It is likely that similar multifunctional molecules exist that could be beneficial in the prevention and treatment of breast cancer. Our laboratory has been investigating one class of multifunctional molecules, derived from a variety of natural product sources, known as sesquiterpene lactones. Perhaps the best known of these is parthenolide, which is the active ingredient in feverfew, a flower that is native to southeastern Europe. Feverfew has traditionally been used to treat headaches, arthritis, and fevers, and it is thought that the anti-inflammatory activity of parthenolide is primarily responsible for its therapeutic effects. More recently, parthenolide has been shown to specifically kill acute and chronic myelogenous leukemia stem cells and prevent skin cancer induction by ultraviolet radiation. In our own studies, we have found that parthenolide treatment of human breast cancer cells rapidly and completely eliminates HDM2, a protein involved in the regulation of the “guardian of the human genome” p53. In addition, parthenolide treatment also eliminated HDAC1, a primary epigenetic silencer of master growth control genes in cancer cells. Neither of these mechanisms had been previously described for parthenolide and neither obviously follows from existing models for parthenolide’s mechanism of action. In order to further develop sesquiterpene lactones as potential therapeutics or chemopreventatives for breast cancer, we now propose to identify those compounds that, at lowest concentration, maximally inhibit proliferation of a variety of breast cancer cells but have minimal effects on normal cells. We will determine what characteristics of breast cancer cells make them more sensitive to these compounds and what aspects of these molecules make them most effective. These studies will lay the framework for future animal-based studies and increase our understanding of how these “aspirins” work to thwart breast cancer from its earliest to its most malignant stages.