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

Kaewpiboon,Chutima; Surapinit,Serm; Malilas,Waraporn; Moon,Jeong; Phuwapraisirisan,Preecha; Tip-Pyang,Santi; Johnston,Randal N.; Koh,Sang Seok; Assavalapsakul,Wanchai; Chung,Young-Hwa

doi:10.3892/ijo.2014.2297

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

Authors:
- Chutima Kaewpiboon
- Serm Surapinit
- Waraporn Malilas
- Jeong Moon
- Preecha Phuwapraisirisan
- Santi Tip-Pyang
- Randal N. Johnston
- Sang Seok Koh
- Wanchai Assavalapsakul
- Young-Hwa Chung
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Affiliations: Program in Biotechnology, Chulalongkorn University, Bangkok 10330, Thailand, BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea, Natural Products Research Unit, Department of Chemistry, Chulalongkorn University, Bangkok 10330, Thailand, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N4N1, Canada, Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, and Department of Functional Genomics, University of Science and Technology, Daejeon 305-333, Republic of Korea, Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Published online on: February 11, 2014 https://doi.org/10.3892/ijo.2014.2297
Pages: 1233-1242

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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.

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