Interleukin-24 (IL-24) is a novel
tumor suppressor/
cytokine gene expressed in normal human melanocytes but for which expression is nearly undetectable in metastatic
melanoma. Overexpression of the
IL-24 protein has been shown to inhibit
tumor cell proliferation and induce apoptosis in many
melanoma cell lines, and is now considered a
tumor suppressor.
Erlotinib, a small-molecule
epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor, has been widely studied for the treatment of human
lung cancer and other solid
tumors, but the
erlotinib-targeted
therapy has not been tested in
melanoma. The objective of this study is to investigate the potency of
erlotinib in suppressing the growth of human
melanoma cells and whether IL-24 could enhance the antitumor activity of
erlotinib. In cell viability and apoptosis assays, treatment with
erlotinib dependently inhibited the growth of different
melanoma cell lines and when combined with adenoviral vector-mediated IL-24 gene therapy, a significant increase in cell growth inhibition and apoptosis induction resulted (P<0.05). Immunoblot assay showed that the combination treatment of
erlotinib and IL-24 considerably increased the cleavage of
caspase-3 and
caspase-9 and the expression of Apaf-1
protein in
melanoma cells, inducing activation of the Apaf-1-dependent apoptotic pathways. Moreover, this combination treatment markedly inhibited phosphorylation of the EGFR, phosphatidylinositol-3
kinase, and Akt
proteins, inactivating the Akt-dependent cell survival signaling pathway. These results show that a combination of IL-24-mediated molecular
therapy and EGFR inhibitors such as
erlotinib may be a promising treatment strategy for human
melanoma and will serve as a basis for guiding the combination treatment designs in future preclinical and clinical trials.