Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity

Raghavendra, Pongali B.; Sreenivasan, Yashin; Manna, Sunil K.

doi:10.1016/j.molimm.2006.11.009

Cited by 52 publications

(47 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data suggest that the uptake of oleandrin in these two different cell lines is likely to account for differential antiproliferative activity. This is consistent with the study reported recently that the human leukemia cell line U-937 is capable of binding oleandrin in the cell membrane, whereas mouse NIH-3T3 cells did not bind oleandrin at all (9). We also examined the expression of α3 isoform protein in Panc-1 cells treated with oleandrin but did not observe any change in protein expression.…”

Section: Discussionsupporting

confidence: 92%

“…Our group and others have observed that human melanoma and leukemia cells were 100-fold more sensitive to oleandrin than were murine tumor cells, normal human epithelial cells, peripheral blood mononuclear cells, or neutrophils (8)(9)(10). Mechanistically, cardiac glycosides bind to the Na, K-ATPase ion exchange pump inhibiting enzymatic activity.…”

Section: Discussionmentioning

confidence: 96%

“…These investigators also observed that oleandrin, as well as digoxin, suppressed the tumor necrosis factor-α/nuclear factor κB signaling pathway by blocking tumor necrosis factor-α-dependent TNFR1/TRADD complex formation (14). Oleandrin has also been shown to induce apoptosis in human leukemia cells by dephosphorylation of Akt, expression of FasL, as well as alteration of membrane fluidity (9). More interestingly, this study also showed that oleandrin binds to the plasma membrane of human lymphoma U937 cells but does not bind to murine NIH3T3 cells (9).…”

Section: Introductionmentioning

confidence: 91%

“…In contrast to its use for the treatment of heart failure, preclinical and retrospective patient data suggest that cardiac glycosides (e.g., digoxin, digitoxin, ouabain, and oleandrin), may reduce the growth of various cancers including breast, lung, prostate, and leukemia (2-7). Recent work from our laboratory and others has shown that these compounds induced selective cell death in certain human but not murine tumor cells (8,9) or normal human cells (10). Previously, we reported that oleandrin and oleandrigenin inhibited proliferation and induced apoptosis due to an increase in intracellular Ca 2+ via inhibition of Na,K-ATPase (5).…”

Section: Introductionmentioning

confidence: 96%

“…Oleandrin has also been shown to induce apoptosis in human leukemia cells by dephosphorylation of Akt, expression of FasL, as well as alteration of membrane fluidity (9). More interestingly, this study also showed that oleandrin binds to the plasma membrane of human lymphoma U937 cells but does not bind to murine NIH3T3 cells (9). Although plausible mechanisms associated with oleandrininduced cell growth suppression in various cancer cells have been proposed, there is only a poor understanding at best of the differential response of human and rodent cancer cells to this and other related cardiac glycosides.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Yang

Menter

Cartwright

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Cardiac glycosides such as oleandrin are known to inhibit the Na,K-ATPase pump, resulting in a consequent increase in calcium influx in heart muscle. Here, we investigated the effect of oleandrin on the growth of human and mouse cancer cells in relation to Na,K-ATPase subunits. Oleandrin treatment resulted in selective inhibition of human cancer cell growth but not rodent cell proliferation, which corresponded to the relative level of Na,K-ATPase α3 subunit protein expression. Human pancreatic cancer cell lines were found to differentially express varying levels of α3 protein, but rodent cancer cells lacked discernable expression of this Na,K-ATPase isoform. A correlation was observed between the ratio of α3 to α1 isoforms and the level of oleandrin uptake during inhibition of cell growth and initiation of cell death; the higher the α3 expression relative to α1 expression, the more sensitive the cell was to treatment with oleandrin. Inhibition of proliferation of Panc-1 cells by oleandrin was significantly reduced when the relative expression of α3 was decreased by knocking down the expression of α3 isoform with α3 siRNA or increasing expression of the α1 isoform through transient transfection of α1 cDNA to the cells. Our data suggest that the relative lack of α3 (relative to α1) in rodent and some human tumor cells may explain their unresponsiveness to cardiac glycosides. In conclusion, the relatively higher expression of α3 with the limited expression of α1 may help predict which human tumors are likely to be responsive to treatment with potent lipid-soluble cardiac glycosides such as oleandrin.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Yang

Menter

Cartwright

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

Ursolic acid induces PC‐3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro

Zhang

Kong

Zeng

et al. 2010

Molecular Carcinogenesis

View full text Add to dashboard Cite

Ursolic acid (UA), a pentacyclic triterpenoid compound, has been demonstrated to have an antiproliferative effect in various tumors. We investigated the cell killing effects of UA in the human hormone refractory prostate cancer cell line, PC-3 cells. Also, the molecular mechanisms underlying its antigrowth effect were explored. We found that UA treatment in vitro can effectively inhibit PC-3 cell viability in a dose-dependent manner by inducing apoptosis, demonstrated by annexin V-FITC/propidium iodide staining. Both extrinsic and intrinsic apoptotic pathways appear to be triggered by UA treatment, because inhibiting activation of both caspase-8 and -9 could prevent UA-induced apoptosis in PC-3 cells. The c-Jun N-terminal kinase (JNK) was found to be activated, followed by Bcl-2 phosphorylation and activation of caspase-9. On the other hand, UA inhibited the Akt pathway, subsequently upregulating the expression of Fas ligand (FasL), which initiates death receptor-mediated apoptosis in PC-3 cells. Importantly, experimentally lowering FasL expression by siRNA significantly inhibited UA-induced caspase-8 activation and at least partly attenuated the consequent apoptosis, suggesting an involvement of FasL and its regulating pathway in the cell killing effect of UA. UA also inhibited cell invasion by downregulating matrix metalloproteinase-9 via inhibition of Akt in PC-3 cells. Although further evaluation of the UA effects in vivo is needed, the present results suggest the potential utility of UA as a novel therapeutic agent in advanced prostate cancer.

show abstract

Cellular location and expression of Na⁺, K⁺-ATPase α subunits affect the anti-proliferative activity of oleandrin

et al. 2012

View full text Add to dashboard Cite

The purpose of this study was to investigate whether intracellular distribution of Na + , K + -ATPase α3 subunit, a receptor for cardiac glycosides including oleandrin, is differentially altered in cancer versus normal cells and whether this altered distribution can be therapeutically targeted to inhibit cancer cell survival. The cellular distribution of Na + , K + -ATPase α3 isoform was investigated in paired normal and cancerous mucosa biopsy samples from patients with lung and colorectal cancers by immunohistochemical staining. The effects of oleandrin on α3 subunit intracellular distribution, cell death, proliferation, and EKR phosphorylation were examined in differentiated and undifferentiated human colon cancer CaCO-2 cells. While Na + , K + -ATPase α3 isoform was predominantly located near the cytoplasmic membrane in normal human colon and lung epithelia, the expression of this subunit in their paired cancer epithelia was shifted to a peri-nuclear position in both a qualitative and quantitative manner. Similarly, distribution of α3 isoform was also shifted from a cytoplasmic membrane location in differentiated human colon cancer CaCO-2 cells HHS Public Access

show abstract

Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity

Cited by 52 publications

References 31 publications

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Ursolic acid induces PC‐3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro

Cellular location and expression of Na⁺, K⁺-ATPase α subunits affect the anti-proliferative activity of oleandrin

Contact Info

Product

Resources

About

Oleandrin induces apoptosis in human, but not in murine cells: Dephosphorylation of Akt, expression of FasL, and alteration of membrane fluidity

Cited by 52 publications

References 31 publications

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase α subunits as drug targets

Ursolic acid induces PC‐3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro

Cellular location and expression of Na+, K+-ATPase α subunits affect the anti-proliferative activity of oleandrin

Contact Info

Product

Resources

About

Cellular location and expression of Na⁺, K⁺-ATPase α subunits affect the anti-proliferative activity of oleandrin