Autophagic Cell Death of Human Pancreatic Tumor Cells Mediated by Oleandrin, a Lipid-Soluble Cardiac Glycoside
Open Access
- 1 December 2007
- journal article
- research article
- Published by SAGE Publications in Integrative Cancer Therapies
- Vol. 6 (4), 354-364
- https://doi.org/10.1177/1534735407309623
Abstract
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.Keywords
This publication has 23 references indexed in Scilit:
- The digitalis-like steroid hormones: New mechanisms of action and biological significanceLife Sciences, 2007
- RETRACTED ARTICLE: Cardiac glycoside induces cell death via FasL by activating calcineurin and NF-AT, but apoptosis initially proceeds through activation of caspasesApoptosis, 2007
- Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidityMolecular Immunology, 2006
- mTOR and cancer therapyOncogene, 2006
- Inhibition of Mammalian Target of Rapamycin or Apoptotic Pathway Induces Autophagy and Radiosensitizes PTEN Null Prostate Cancer CellsCancer Research, 2006
- Cardiac Glycosides Initiate Apo2L/TRAIL-Induced Apoptosis in Non–Small Cell Lung Cancer Cells by Up-regulation of Death Receptors 4 and 5Cancer Research, 2006
- Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs?Breast Cancer Research and Treatment, 2005
- The role of autophagy in cancer development and response to therapyNature Reviews Cancer, 2005
- Role and Regulation of Starvation-Induced Autophagy in the Drosophila Fat BodyDevelopmental Cell, 2004
- Digitoxin is a potential anticancer agent for several types of cancerMedical Hypotheses, 1999