15-methylene eburnamonine: A novel therapeutic agent against metastatic breast cancer
One in eight women in the United States will develop invasive breast cancer in her lifetime. Of these women, a significant number will develop metastases to the brain (10-16%) and to the bone (60-70%) resulting in poor prognosis and significant morbidity. Currently, there are no effective therapies against breast to brain and breast to bone metastases. One of the reasons is the tumor microenvironment which is responsible for increased tumor cell proliferation and survival leading to drug resistance. Another reason are the tumor propagating cells (TPCs) which are reputed to be the cause of metastatic spread in many solid tumors, including those of the breast. A successful therapeutic agent must target cancer cells, as well as TPCs while having minimal toxicity against normal tissue. Eburnamonine (EBN), a natural product derived from the Dwarf Periwinkle. It has been found to cross the blood-brain-barrier and target the central nervous system in boosting learning and memory function, as well as a treatment against brain ischemia and anoxia. EBN also has cytotoxic activity against leukemia cells. In addition, EBN has no known toxicities. A derivative of EBN, 15-Methylene eburnamonine (15-M-EBN), was synthesized by Professor David Colby's laboratory in the Department of Medicinal Chemistry and Molecular Pharmacy at Purdue University. This derivative, 15-M-EBN, contained an enone group which has been found to contribute to the cytotoxicity of cancer cells through oxidative stress in another compound, Parthenolide. We tested the cytotoxicity of 15-M-EBN against metastatic breast cancer cells and their brain seeking and bone seeking counterparts. 15-M-EBN was also evaluated as a target against TPCs in metastatic breast cancer cell lines as well as in mice. Furthermore, 15-M-EBN was found to be biologically active against cancer cells in the presence of key components of the brain, bone, and mammary gland microenvironments. 15-M-EBN was found to induce apoptosis in cancer cells through upregulation of oxidative stress which led to mitochondrial depolarization, cytochrome C release and subsequent caspase 6 and 7 activation. We also tested 15-M-EBN against cell lines in other cancers: prostate, multiple myeloma, and glioblastoma multiforme. 15-M-EBN was found to be cytotoxic against these cell lines as well. Taken together, 15-M-EBN has significant potential to be a therapeutic agent against metastatic breast cancer.
Kirshner, Purdue University.
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