Autophagic Cell Death of Human Pancreatic Tumor Cells Mediated by Oleandrin, a Lipid-Soluble Cardiac Glycoside
| Autor: | Yasuko Kondo, Robert A. Newman, Diana Chan, Susan Dixon, Peiying Yang, Carrie Cartwright, Mary Johansen, Tomohisa Yokoyama |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
0301 basic medicine
Oleandrin Programmed cell death Blotting Western Cell Antineoplastic Agents Biology Transfection Cardiac Glycosides 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Microscopy Electron Transmission Cell Line Tumor Autophagy medicine Humans Organic Chemicals Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein Kinase Inhibitors Cell Proliferation Cardiac glycoside Dose-Response Relationship Drug Molecular Structure Cell growth Cell Cycle Cell cycle Lipids Mitochondria Cell biology Pancreatic Neoplasms Cardenolides 030104 developmental biology medicine.anatomical_structure Solubility Complementary and alternative medicine Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Microtubule-Associated Proteins Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Integrative Cancer Therapies. 6:354-364 |
| ISSN: | 1552-695X 1534-7354 |
| DOI: | 10.1177/1534735407309623 |
| Popis: | Lipid-soluble cardiac glycosides such as bufalin, oleandrin, and digitoxin have been suggested as potent agents that might be useful as anticancer agents. Past research with oleandrin, a principle cardiac glycoside in Nerium oleander L. (Apocynaceae), has been shown to induce cell death through induction of apoptosis. In PANC-1 cells, a human pancreatic cancer cell line, cell death occurs not through apoptosis but rather through autophagy. Oleandrin at low nanomolar concentrations potently inhibited cell proliferation associated with induction of a profound G2/M cell cycle arrest. Inhibition of cell cycle was not accompanied by any significant sub G1 accumulation of cells, suggesting a nonapoptotic mechanism. Oleandrin-treated cells exhibited time- and concentration-dependent staining with acridine orange, a lysosomal stain. Subcellular changes within PANC-1 cells included mitochondrial condensation and translocation to a perinuclear position accompanied by vacuoles. Use of a fluorescent oleandrin analog (BODIPY-oleandrin) revealed co-localization of the drug within cell mitochondria. Damaged mitochondria were found within autophagosome structures. Formation of autophagosomes was confirmed through electron microscopy and detection of green fluorescent protein—labeled light chain 3 association with autophagosome membranes. Also observed was a drug-mediated inhibition of pAkt formation and up-regulation of pERK. Transfection of Akt into PANC-1 cells or inhibition of pERK activation by MAPK inhibitor abrogated oleandrin-mediated inhibition of cell growth, suggesting that the reduction of pAkt and increased pERK are important to oleandrin's ability to inhibit tumor cell proliferation. The data provide insight into the mechanisms and role of a potent, lipid-soluble cardiac glycoside (oleandrin) in control of human pancreatic cancer proliferation. |
| Databáze: | OpenAIRE |
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