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Synergy between enzastaurin doxorubicin in inducing melanoma apoptosis
Author(s) -
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
Publication year - 2013
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12144
Subject(s) - doxorubicin , melanoma , apoptosis , pharmacology , cytotoxicity , cell growth , cancer research , chemistry , medicine , chemotherapy , in vitro , biochemistry
Summary 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 G 361, SK ‐ MEL 3, A375 and SAN . Enzastaurin IC 50 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 TNF α, whereas enzastaurin‐stimulated TNFR ‐1 expression on plasma membrane. The effect on TNFR ‐1 appeared to be mediated by PKC ζ 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.