Spirooxindole derivative SOID-8 induces apoptosis associated with inhibition of JAK2/STAT3 signaling in melanoma cells.
Spirooxindole derivative SOID-8 induces apoptosis associated with inhibition of JAK2/STAT3 signaling in melanoma cells.
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DOI：
10.1371/journal.pone.0049306
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jove R
中科院分区：
文献类型：
--
作者：
Tian Y;Nam S;Liu L;Yakushijin F;Yakushijin K;Buettner R;Liang W;Yang F;Ma Y;Horne D;Jove R
黑色素瘤一般对目前的化疗方案不耐药，因此需要新的治疗策略。在本研究中，我们合成了一系列螺氧吲哚衍生物(SOID-1至SOID-12)，并评价了它们对黑色素瘤的抗肿瘤作用。活性筛选表明，在12个螺氧吲哚类化合物中，SOID-8具有最强的抗肿瘤活性。SOID-8对人黑色素瘤细胞A2058、A375、SK-Mel-5和SK-Mel-28的生长抑制作用呈剂量和时间依赖性。SOID-8还可诱导肿瘤细胞凋亡，Annexin V染色阳性和多聚ADP-核糖聚合酶裂解增加证实了这一点。抗凋亡蛋白Mcl-1是Bcl2家族的成员，其表达下调与SOID-8诱导的细胞凋亡有关。此外，SOID-8还以剂量和时间依赖的方式降低信号转导和转录激活因子3(STAT3)的酪氨酸磷酸化。这种抑制与Janus激活的激酶-2(JAK2)的磷酸化水平降低有关，JAK2是一种上游激酶，在Tyr705处介导STAT3的磷酸化。因此，SOID-8抑制IL-6诱导的黑色素瘤细胞中STAT3和JAK2的激活。最后，SOID-8抑制了小鼠移植瘤模型中黑色素瘤的生长，同时降低了JAK2和STAT3的磷酸化。我们的结果表明，SOID-8的抗肿瘤活性至少部分是由于抑制了黑色素瘤细胞中的JAK2/STAT3信号转导。这些发现表明，螺氧吲哚衍生物SOID-8是一种很有前途的先导化合物，可用于进一步开发新的黑色素瘤预防和治疗药物。
Melanoma is generally refractory to current chemotherapy, thus new treatment strategies are needed. In this study, we synthesized a series of spirooxindole derivatives (SOID-1 to SOID-12) and evaluated their antitumor effects on melanoma. Among the 12 spirooxindole derivatives, SOID-8 showed the strongest antitumor activity by viability screening. SOID-8 inhibited viability of A2058, A375, SK-MEL-5 and SK-MEL-28 human melanoma cells in a dose- and time-dependent manner. SOID-8 also induced apoptosis of these tumor cells, which was confirmed by positive Annexin V staining and an increase of poly(ADP-ribose) polymerase cleavage. The antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was downregulated and correlated with SOID-8 induced apoptosis. In addition, SOID-8 reduced tyrosine phosphorylation of Signal Tansducer and Activator of Transcription 3 (STAT3) in both dose- and time-dependent manners. This inhibition was associated with decreased levels of phosphorylation of Janus-activated kinase-2 (JAK2), an upstream kinase that mediates STAT3 phosphorylation at Tyr705. Accordingly, SOID-8 inhibited IL-6-induced activation of STAT3 and JAK2 in melanoma cells. Finally, SOID-8 suppressed melanoma tumor growth in a mouse xenograft model, accompanied with a decrease of phosphorylation of JAK2 and STAT3. Our results indicate that the antitumor activity of SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells. These findings suggest that the spirooxindole derivative SOID-8 is a promising lead compound for further development of new preventive and therapeutic agents for melanoma.
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影响因子：
15
作者：
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通讯作者：
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影响因子：
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作者：
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