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.

Autophagy and multidrug resistance in cancer

“…Interestingly, inhibition of autophagy by Beclin1 siRNA could eliminate Feroniellin A-induced apoptosis. Moreover, further stimulation of autophagy by rapamycin accelerates Feroniellin A-induced apoptosis [90]. Coincidentally, autophagy induced by metformin could also assists TRAIL-mediated apoptosis in TRAIL-resistant lung adenocarcinoma.…”

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets

“…Thus, markers to indicate which outcome would result must be identified before this line of targeting can be considered. Recently, a number of natural products were shown to be modulators of autophagy, such as bafilomycin A1 [88,89], feroniellin A [90] and oblongifolin C [91]. …”

“…In chronic myelogenous leukemia (CML) [90], for example, the breakpoint cluster region/Abelson (Bcr-Abl) translocation appears at the beginning of the hematopoietic differentiation tree [114], implying an intimate relationship between SC, mutation, and tumor development. In some cancers, germline mutations in tissue SC (e.g., in colon cancer and medulloblastoma) also suggest a central role for these cells in tumor pathogenesis [115,116].…”

Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells

“…The autophagy inhibitor bafilomycin A1 decreased jujuboside B-induced cell viability, as indicated [248]. Feroniellin A (FERO), a novel furanocoumarin, was shown to induce autophagy, associated with LC3B-I to LC3B-II conversion, induction of GFP-LC3B puncta, enhanced expression of BECN1 and ATG5, and inactivation of mTOR in etoposide-resistant human lung carcinoma A549RT-eto cells [249]. Silencing of BECN1 by siRNA reduced FERO-induced apoptosis in A549RT-eto cells and activation of autophagy by rapamycin accelerated FERO-induced apoptosis [249].…”