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Cardiac Glycosides as Novel Cancer Therapeutic Agents
Table 2.
Reported Mechanisms of Cardiac Glycoside–Mediated Inhibition of Tumor Cell Proliferation
| Compound | Proposed antiproliferative mechanism(s) | Reference |
|---|---|---|
| NF-κB, Nuclear Factor-kappaB; JNK, c-Jun NH2-terminal kinase; AP-1, Activator Protein-1; FasL, Fas ligand; ROS, reactive oxygen species; FGF-2, Fibroblast Growth Factor 2; IL-8, Interleukin-8; TNF-α, Tumor Necrosis Factor α; TRAIL, (TNF)-related apoptosis-inducing ligand; NF-AT, Nuclear Factor of Activated T cells; MAPKs, mitogen-activated protein kinases. | ||
| Oleandrin | Alteration of membrane fluidity | (15, 35, 97, 100) |
| Decreased activation of nuclear transcription factors NF-κB, JNK, and AP-1 | (19, 98) | |
| Increased intracellular calcium | (17, 50) | |
| Increased expression of FasL | (99) | |
| Increased ROS production, oxidative injury, and mitochondrial injury | (50, 51, 58) | |
| Decreased phosphorylation of Akt | (17, 36, 57) | |
| Inhibition of cellular transport of tumor growth factors (FGF-2) | (100) | |
| Down regulation of IL-8 receptors | (99) | |
| Initiates Apo2L/TRAIL apoptosis via increased expression of death receptors 4 and 5 | (18, 48) | |
| Activation of calcineurin and nuclear transcription factor NF-AT | (99) | |
| Bufalin | Increased activation of MAPKs | (101–103) |
| Decreased cAMP content | (5) | |
| Inhibition of topoisomerases I and II | (17, 104, 105) | |
| Induction of differentiation in human myeloid leukemia | (106, 107) | |
| Downregulation of cyclin A, Bcl-2 and Bcl-xL; Increased expression of p21 and Bax | (7, 104, 108) | |
| Ouabain, Digitoxin | Loss of mitochondrial membrane potential; increase Par-4 expression | (17, 109) |
| Increased Ca2+ uptake | (15, 16, 110, 111) | |
| Acts as an estrogen receptor antagonist | (15, 112) | |
| Sustained ROS production | (29, 31, 111) | |
| Regulates expression of cell tight junctions and adhesion molecules | (16, 17, 55) | |
| Selective protein kinase C activation leading to differentiation | (17, 113) | |
| Increased activation of MAPKs | (16, 113, 114) | |
| Reduction in anti-apoptotic proteins Bcl-xL and Bcl-2 | (114–116) | |
| Increased cytochrome c release and caspase activation | (28, 114, 116) | |
| Inhibition of topoisomerase I | (28, 61, 117, 118) | |
| Block activation of the TNF-α/NF-κB signaling pathway | (59, 119) | |
| UNBS1450 | Decreased heat shock protein (Hsp70) | (59, 120) |
| Increased permeabilization of lyososomal membrane | (120) | |
| Block activation of the TNF-α/NF-κB signaling pathway | (59) | |
