Synergy between enzastaurin and doxorubicin in inducing melanoma apoptosis.
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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Medical and Biotech [MESH] Definitions
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.