Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells

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Title
Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells
Author(s)
C Kaewpiboon; S Surapinit; W Malilas; J Moon; P Phuwapraisirisan; S Tip-Pyang; R N Johnston; Sang Seok Koh; W Assavalapsakul; Y H Chung
Bibliographic Citation
International Journal of Oncology, vol. 44, no. 4, pp. 1233-1242
Publication Year
2014
Abstract
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-κB, 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-κB, accelerated apoptosis of A549RT-eto cells through decreased expression of P-gp, indicating that NF-κB 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.
Keyword
ApoptosisAutophagyFeroniellin AMultidrug resistance
ISSN
1019-6439
Publisher
Spandidos Publ Ltd
DOI
http://dx.doi.org/10.3892/ijo.2014.2297
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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