Feroniellin A- induced autophagy causes apoptosis in multidrug- resistant human A549 lung cancer cells
Feroniellin A- induced autophagy causes apoptosis in multidrug- resistant human A549 lung cancer cells
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DOI：
10.3892/ijo.2014.2297
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发表时间：
2014-04-01
影响因子：
5.2
通讯作者：
Chung, Young-hwa
中科院分区：
文献类型：
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作者：
Kaewpiboon, Chutima;Surapinit, Serm;Chung, Young-hwa
在筛选能够逆转对依托泊苷耐药的人A549肺癌细胞（A549 RT-eto）多药耐药的天然化合物的过程中，我们发现新的呋喃香豆素Feroniellin A（FERO）以剂量和时间依赖性的方式显示对A549 RT-eto细胞的毒性。FERO降低NF-B的表达，导致由MDR 1编码的P-糖蛋白（P-gp）下调，最终使A549 RT-eto细胞对凋亡敏感。FERO特异性降低MDR 1的转录和启动子活性，但不抑制其他多药耐药基因MRP 2和BCRP的表达。此外，FERO与NF-B抑制剂Bay 11 -7802共同给药通过降低P-gp表达加速A549 RT-eto细胞凋亡，表明NF-B参与多药耐药。相反，添加Z-VAD（一种泛半胱天冬酶抑制剂）可阻断A549 RT-eto细胞中FERO诱导的凋亡，但不能阻断P-gp的下调，表明P-gp表达的降低是FERO诱导的凋亡所必需的，但不是充分的。有趣的是，我们发现FERO也诱导自噬，其特征在于LC 3 I转化为LC 3 II，诱导GFP-LC 3斑点，增强Beclin-1和ATG 5的表达，以及mTOR的失活。此外，通过siRNA抑制Beclin-1减少了A549 RT-eto细胞中FERO诱导的凋亡，并且雷帕霉素激活自噬加速了FERO诱导的凋亡，表明自噬在FERO诱导的凋亡中起着积极的作用。在此，我们报告，FERO逆转A549 RT-eto细胞的多药耐药性，并通过诱导自噬和凋亡发挥其细胞毒性作用，这表明FERO可以是一个有用的抗癌药物多药耐药肺癌。
During the screening of natural chemicals that can reverse multidrug resistance in human A549 lung cancer cells resistant to etoposide (A549RT-eto), we discovered that Feroniellin A (FERO), a novel furanocoumarin, shows toxicity toward A549RT-eto cells in a dose- and time-dependent manner. FERO reduced the expression of NF-B, leading to downregulation of P-glycoprotein (P-gp), encoded by MDR1, which eventually sensitized A549RT-eto cells to apoptosis. FERO specifically diminished transcription and promoter activity of MDR1 but did not inhibit the expression of other multidrug resistance genes MRP2 and BCRP. Moreover, co-administration of FERO with Bay11-7802, an inhibitor of NF-B, accelerated apoptosis of A549RT-eto cells through decreased expression of P-gp, indicating that NF-B is involved in multidrug resistance. Conversely, addition of Z-VAD, a pan-caspase inhibitor, blocked FERO-induced apoptosis in A549RT-eto cells but did not block downregulation of P-gp, indicating that a decrease in P-gp expression is necessary but not sufficient for FERO-induced apoptosis. Interestingly, we found that FERO also induces autophagy, which is characterized by the conversion of LC3 I to LC3 II, induction of GFP-LC3 puncta, enhanced expression of Beclin-1 and ATG5, and inactivation of mTOR. Furthermore, suppression of Beclin-1 by siRNA reduced FERO-induced apoptosis in A549RT-eto cells and activation of autophagy by rapamycin accelerated FERO-induced apoptosis, suggesting that autophagy plays an active role in FERO-induced apoptosis. Herein, we report that FERO reverses multidrug resistance in A549RT-eto cells and exerts its cytotoxic effect by induction of both autophagy and apoptosis, which suggests that FERO can be a useful anticancer drug for multidrug-resistant lung cancer.