Lev Dina Chelouche, Ruiz Maribelis, Mills Lisa, McGary Eric C, Price Janet E, Bar-Eli Menashe
Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mol Cancer Ther. 2003 Aug;2(8):753-63.
The incidence of cutaneous malignant melanoma in the United States has increased more than any other cancer in recent years. Chemotherapy for metastatic melanoma is disappointing, there being anecdotal cases of complete remission. Dacarbazine (DTIC) is considered the gold standard for treatment, having a response rate of 15-20%, but most responses are not sustained. The mechanisms for the increased chemotherapeutic resistance of melanoma are unclear. The objective of this study was to determine the mechanisms by which melanoma cells escape the cytotoxic effect of DTIC. Here, we show that DTIC induced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) protein overexpression and secretion via transcriptional up-regulation in the two melanoma cell lines SB-2 and MeWo. Luciferase activity driven by the IL-8 and VEGF promoters was up-regulated by 1.5-2- and 1.6-3.5-fold, respectively, in the SB2 and MeWo melanoma cell lines. The mitogen-activated protein kinase signal transduction pathway seemed to regulate at least partially the activation of IL-8, whereas it was not involved in VEGF promoter regulation. Electrophoretic mobility shift analysis analyses have revealed an increase in binding activity of activator protein 1 (c-Jun) and nuclear factor-kappaB after DTIC treatment for both melanoma cell lines. Metastatic melanoma cell lines secreting high levels of IL-8 and VEGF were more resistant to DTIC than early primary melanomas secreting low levels of the cytokines. In addition, transfection of the primary cutaneous melanoma SB-2 cells with the IL-8 gene rendered them resistant to the cytotoxic effect of the drug, whereas the addition of IL-8-neutralizing antibody to metastatic melanoma cells lowered their sensitivity to DTIC. Taken together, our data demonstrate that DTIC can cause melanoma cells to secrete IL-8 and VEGF, which might render them resistant to the cytotoxic effects of the drug. We propose that combination treatment with anti-VEGF/IL-8 agents may potentiate the therapeutic effects of DTIC.
近年来，美国皮肤恶性黑色素瘤的发病率增长幅度超过了其他任何癌症。转移性黑色素瘤的化疗效果令人失望，仅有个别完全缓解的病例报道。达卡巴嗪（DTIC）被视为治疗的金标准，其有效率为15% - 20%，但多数疗效难以持久。黑色素瘤化疗耐药性增加的机制尚不清楚。本研究的目的是确定黑色素瘤细胞逃避DTIC细胞毒性作用的机制。在此，我们发现DTIC通过转录上调诱导了白细胞介素（IL）-8和血管内皮生长因子（VEGF）蛋白的过表达及分泌，在两种黑色素瘤细胞系SB - 2和MeWo中均如此。在SB2和MeWo黑色素瘤细胞系中，由IL - 8和VEGF启动子驱动的荧光素酶活性分别上调了1.5 - 2倍和1.6 - 3.5倍。丝裂原活化蛋白激酶信号转导通路似乎至少部分调节了IL - 8的激活，而它不参与VEGF启动子的调节。电泳迁移率变动分析显示，两种黑色素瘤细胞系经DTIC处理后，激活蛋白1（c - Jun）和核因子 - κB的结合活性均增加。分泌高水平IL - 8和VEGF的转移性黑色素瘤细胞系比分泌低水平细胞因子的早期原发性黑色素瘤对DTIC更具耐药性。此外，用IL - 8基因转染原发性皮肤黑色素瘤SB - 2细胞使其对药物的细胞毒性作用产生耐药性，而向转移性黑色素瘤细胞中添加IL - 8中和抗体则降低了它们对DTIC的敏感性。综上所述，我们的数据表明DTIC可导致黑色素瘤细胞分泌IL - 8和VEGF，这可能使它们对药物的细胞毒性作用产生耐药性。我们建议联合使用抗VEGF/IL - 8药物可能会增强DTIC的治疗效果。
