Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.
Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells.
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DOI：
10.18632/oncotarget.5064
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发表时间：
2015-09-29
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;Baxter RD;Hunt KM;Agarwal J;Elmets CA;Athar M;Afaq F
黑色素瘤是最致命的皮肤恶性肿瘤，其发病率在全球范围内呈上升趋势。在黑色素瘤中，BRAF/MEK/ERK(MAPK)和PI3K/AKT/mTOR(PI3K)信号通路的结构性激活在细胞增殖、生存和肿瘤发生中起着关键作用。这些关键信号通路的最佳阻断的化合物组合可能为黑色素瘤的预防和治疗提供有效的策略。已知的植物化学物质非瑟素具有抗增殖和促细胞凋亡的活性。我们发现Fesetin处理抑制了黑色素瘤细胞中的PI3K信号通路。因此，我们研究了非瑟素和索拉非尼(RAF抑制剂)单独和联合使用对细胞增殖、凋亡和肿瘤生长的影响。与单独用药相比，联合治疗(非瑟丁+索拉非尼)在较低剂量下更有效地减少了BRAF突变的人类黑色素瘤细胞的生长。此外，联合用药还可促进(1)细胞凋亡，(2)caspase-3和PARP的切割，(3)Bax和Bak的表达，(4)抑制bcl2和Mcl-1的表达，(5)抑制PI3K的表达，抑制MEK1/2、ERK1/2、AKT和mTOR的表达。在裸鼠皮下植入黑色素瘤细胞(A375和SK-MEL-28)的实验中，我们发现，与单独使用药物相比，联合治疗导致了更大的肿瘤生长抑制。此外，联合治疗在抑制移植瘤的增殖和血管生成，诱导细胞凋亡，以及抑制MAPK和PI3K通路方面比单一治疗更有效。这些数据表明，联合使用非瑟丁和索拉非尼同时抑制这两个信号通路可能是治疗黑色素瘤的一种选择。
Melanoma is the most deadly form of cutaneous malignancy, and its incidence rates are rising worldwide. In melanoma, constitutive activation of the BRAF/MEK/ERK (MAPK) and PI3K/AKT/mTOR (PI3K) signaling pathways plays a pivotal role in cell proliferation, survival and tumorigenesis. A combination of compounds that lead to an optimal blockade of these critical signaling pathways may provide an effective strategy for prevention and treatment of melanoma. The phytochemical fisetin is known to possess anti-proliferative and pro-apoptotic activities. We found that fisetin treatment inhibited PI3K signaling pathway in melanoma cells. Therefore, we investigated the effect of fisetin and sorafenib (an RAF inhibitor) alone and in combination on cell proliferation, apoptosis and tumor growth. Combination treatment (fisetin + sorafenib) more effectively reduced the growth of BRAF-mutated human melanoma cells at lower doses when compared to individual agents. In addition, combination treatment resulted in enhanced (i) apoptosis, (ii) cleavage of caspase-3 and PARP, (iii) expression of Bax and Bak, (iv) inhibition of Bcl2 and Mcl-1, and (v) inhibition of expression of PI3K, phosphorylation of MEK1/2, ERK1/2, AKT and mTOR. In athymic nude mice subcutaneously implanted with melanoma cells (A375 and SK-MEL-28), we found that combination therapy resulted in greater reduction of tumor growth when compared to individual agents. Furthermore, combination therapy was more effective than monotherapy in: (i) inhibition of proliferation and angiogenesis, (ii) induction of apoptosis, and (iii) inhibition of the MAPK and PI3K pathways in xenograft tumors. These data suggest that simultaneous inhibition of both these signaling pathways using combination of fisetin and sorafenib may serve as a therapeutic option for the management of melanoma.