title: Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells.
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.
authors.affiliation: Program in Biotechnology, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Chutima
authors.initials: C
authors.lastname: Kaewpiboon
authors.affiliation: Program in Biotechnology, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Serm
authors.initials: S
authors.lastname: Surapinit
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Waraporn
authors.initials: W
authors.lastname: Malilas
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Moon
authors.affiliation: Natural Products Research Unit, Department of Chemistry, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Preecha
authors.initials: P
authors.lastname: Phuwapraisirisan
authors.affiliation: Natural Products Research Unit, Department of Chemistry, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Santi
authors.initials: S
authors.lastname: Tip-Pyang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N4N1, Canada.
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.affiliation: 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.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.affiliation: Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Wanchai
authors.initials: W
authors.lastname: Assavalapsakul
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1; D045744:Cell Line, Tumor; D003374:Coumarins / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008565:Membrane Proteins / Q000235:genetics; D008840:Microfilament Proteins; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D020123:Sirolimus / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014158:Transcription, Genetic
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D003374:Coumarins; D005663:Furans; D006027:Glycosides; C412617:KLHL1 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009570:Nitriles; C498143:RELA protein, human; D034741:RNA, Small Interfering; D013450:Sulfones; D051996:Transcription Factor RelA; C533509:feronielloside; D005047:Etoposide; D020123:Sirolimus