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- Title
Synergy between enzastaurin doxorubicin in inducing melanoma apoptosis.
- Authors
Romano, Simona; Nappo, Giovanna; Calì, Gaetano; Wang, Samuel Y.‐S.; Staibano, Stefania; D'Angelillo, Anna; Ilardi, Gennaro; Sorrentino, Antonio; Di Pace, Anna Laura; Siano, Maria; Bisogni, Rita; Romano, Maria Fiammetta
- Abstract
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 3 μM 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 ≥1 μM. 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 plasma membrane. The effect on TNFR-1 appeared to be mediated by PKCζ inhibition. Taken together, our findings suggest that enzastaurin increases doxorubicin-induced apoptosis of melanoma by a mechanism involving, at least in part, activation of the TNF-α signal.
- Subjects
MELANOMA treatment; DOXORUBICIN; APOPTOSIS; CANCER chemotherapy; CELL lines; CANCER cells; CELL-mediated cytotoxicity; TUMOR necrosis factors
- Publication
Pigment Cell & Melanoma Research, 2013, Vol 26, Issue 6, p900
- ISSN
1755-1471
- Publication type
Article
- DOI
10.1111/pcmr.12144