Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.
Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma.
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DOI：
10.18632/oncotarget.6237
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发表时间：
2016-01-12
期刊：
影响因子：
--
通讯作者：
Afaq F
中科院分区：
文献类型：
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作者：
Pal HC;Diamond AC;Strickland LR;Kappes JC;Katiyar SK;Elmets CA;Athar M;Afaq F
黑色素瘤是最具侵略性和致命形式的皮肤肿瘤，由于其倾向于转移。致癌性BRAF驱动BRAF/MEK/ERK（MAPK）通路的持续激活，并与PI 3 K/AKT/mTOR（PI 3 K）信号传导合作以诱导上皮向间充质转化（EMT），导致细胞侵袭和转移。因此，靶向这些途径是一种有前途的预防/治疗策略。我们已经表明，非瑟酮，类黄酮，减少人类黑色素瘤细胞的侵袭，抑制EMT。此外，非瑟酮通过下调PI 3 K通路抑制黑色素瘤细胞增殖和肿瘤生长。在这项研究中，我们的目的是确定非瑟酮是否可以加强索拉非尼在BRAF突变的黑色素瘤中的抗侵袭和抗转移作用。我们发现，联合治疗（非瑟酮+索拉非尼）更有效地减少BRAF突变的黑色素瘤细胞在体外和筏培养的迁移和侵袭相比，单独的代理。联合治疗还有效地抑制EMT，如通过体外和异种移植肿瘤中N-钙粘蛋白、波形蛋白和纤连蛋白的减少和E-钙粘蛋白的增加所观察到的。此外，与单药治疗相比，联合治疗有效抑制了Snail 1、Twist 1、Slug和ZEB 1蛋白表达。MMP-2和MMP-9在异种移植肿瘤中的表达在组合治疗中与单独的药剂相比进一步降低。无胸腺小鼠的生物发光成像，静脉注射稳定转染的CMV-荧光素酶-虹膜-嘌呤霉素。EGFP标记的A375黑色素瘤细胞在联合治疗后与单一治疗相比表现出更少的肺转移。我们的研究结果表明，非瑟酮增强索拉非尼的抗侵袭和抗转移作用。我们的数据表明，非瑟酮可能是一个值得的辅助化疗的管理黑色素瘤。
Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin. T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.