论文标题
一种新型的BIS-Coumarin靶向黑色素瘤关键信号通路的多种酪氨酸激酶，并抑制黑色素瘤细胞的存活，增殖和迁移
A Novel Bis-Coumarin Targets Multiple Tyrosine Kinases of Key Signaling Pathways in Melanoma and Inhibits Melanoma Cell Survival, Proliferation, and Migration
论文作者
论文摘要
黑色素瘤是最危险的皮肤恶性肿瘤之一，由于其高转移性趋势和高死亡率。强化黑色素瘤进展的关键信号通路的激活取决于酪氨酸激酶的磷酸化和氧化应激。我们在这里研究了新的BIS-Coumarin衍生物（3,5-DCPBC）对人黑色素瘤细胞存活，生长，增殖，迁移和细胞内氧化还原状态以及破译相关信号途径的影响。这种新型衍生物被发现对黑色素瘤细胞有毒，对它们的良性对应物，黑色素细胞和成纤维细胞无毒。 3,5-DCPBC通过深刻抑制表皮生长因子受体的磷酸化以及相关的下游途径，抑制了不同转移性和非转移性黑色素瘤细胞系的细胞存活，迁移和非转移性黑色素瘤细胞系。抑制关键下游转录因子和不同酪氨酸激酶的磷酸化包括JAK/STAT，SRC激酶，ERK和MAP激酶（p38alpha），均参与黑色素瘤进展。多种酪氨酸激酶和黑色素瘤细胞中相应的关键基因的同时和特异性靶向使3,5-DCPBC成为一个非常有趣的抗叶绿素瘤，以及抗激素候选药物，从长远来看，在晚期黑色素瘤疗法中可能会有希望。
Melanoma is one of the most dangerous skin malignancies due to its high metastatic tendency and high mortality. Activation of key signaling pathways enforcing melanoma progression depends on phosphorylation of tyrosine kinases, and oxidative stress. We here investigated the effect of the new bis-coumarin derivative (3,5-DCPBC) on human melanoma cell survival, growth, proliferation, migration, and intracellular redox state, and deciphered associated signal pathways. This novel derivative was found to be toxic for melanoma cells, and non-toxic for their benign counterparts, melanocytes and fibroblasts. 3,5-DCPBC inhibited cell survival, migration and proliferation of different metastatic, and non-metastatic melanoma cell lines through the profound suppression of phosphorylation of the Epidermal Growth Factor receptor, and related downstream pathways. Suppression of phosphorylation of key downstream transcription factors and different tyrosine kinases comprise JAK/STAT, SRC kinases, ERK and MAP kinases (p38alpha), all involved in melanoma progression. Simultaneous and specific targeting of multiple tyrosine kinases and corresponding key genes in melanoma cells makes 3,5-DCPBC a highly interesting anti-melanoma, and anti-metastatic drug candidate which may in the long term hold promise in the therapy of advanced melanoma.
