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Melanoma is resistant to most standard chemotherapeutics. We analysed the combined effect of doxorubicin and enzastaurin on cell death of four melanoma cell lines, namely G361, SK-MEL3, A375 and SAN. Enzastaurin IC50 was calculated by measure of growth inhibition with MTS assay and corresponded to 2 μM; the half maximal cytotoxicity of doxorubicin was obtained at 3μM dose. Evaluation of combination index showed synergism (CI>1) or additive effect (CI=1) with all melanoma cell lines, with enzastaurin doses >0.6 μM and doxorubicin doses > 1μM. Combination of the two drugs resulted in increase in caspase 3 and 8 activation, in comparison with activation by single agents. Caspase 8 activation was impaired by TNFR-1 blocking. Our results show doxorubicin stimulated production of TNFα, whereas enzastaurin stimulated TNFR-1 expression on plasmamembrane. The effect on TNFR-1 appeared to be mediated by PKCζ inhibition. Taken together, our findings suggest enzastaurin increases doxorubicin-induced apoptosis of melanoma by a mechanism involving, at least in part, activation of the TNF-α signal. This article is protected by copyright. All rights reserved.
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Federico II University, Napoli, Italy.
This article was published in the following journal.
Name: Pigment cell & melanoma research
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Tumor necrosis factor receptor family members that are widely expressed and play a role in regulation of peripheral immune responses and APOPTOSIS. The receptors are specific for TNF-RELATED APOPTOSIS-INDUCING LIGAND and signal via conserved death domains that associate with specific TNF RECEPTOR-ASSOCIATED FACTORS in the CYTOPLASM.
A transmembrane-protein belonging to the TNF family of intercellular signaling proteins. It is a widely expressed ligand that activates APOPTOSIS by binding to TNF-RELATED APOPTOSIS-INDUCING LIGAND RECEPTORS. The membrane-bound form of the protein can be cleaved by specific CYSTEINE ENDOPEPTIDASES to form a soluble ligand form.
An unpigmented malignant melanoma. It is an anaplastic melanoma consisting of cells derived from melanoblasts but not forming melanin. (Dorland, 27th ed; Stedman, 25th ed)
A secreted tumor necrosis factor receptor family member that has specificity for TNF-RELATED APOPTOSIS-INDUCING LIGAND. It plays a modulating role in activation of APOPTOSIS signaling.
A flavoprotein that functions as a powerful antioxidant in the MITOCHONDRIA and promotes APOPTOSIS when released from the mitochondria. In mammalian cells AIF is released in response to pro-apoptotic protein members of the bcl-2 protein family. It translocates to the CELL NUCLEUS and binds DNA to stimulate CASPASE-independent CHROMATIN condensation.
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