The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells

Abstract

Koelreuteria henryi Dummer, an endemic plant of Taiwan, has been used as a folk medicine for the treatment of hepatitis, enteritis, cough, pharyngitis, allergy, hypertension, hyperlipidemia, and cancer. Austrobailignan-1, a natural lignan derivative isolated from Koelreuteria henryi Dummer, has anti-oxidative and anti-cancer properties. However, the effects of austrobailignan-1 on human cancer cells have not been studied yet. Here, we showed that austrobailignan-1 inhibited cell growth of human non-small cell lung cancer A549 and H1299 cell lines in both dose- and time-dependent manners, the IC50 value (48 h) of austrobailignan-1 were 41 and 22 nM, respectively. Data from flow cytometric analysis indicated that treatment with austrobailignan-1 for 24 h retarded the cell cycle at the G2/M phase. The molecular event of austrobailignan-1-mediated G2/M phase arrest was associated with the increase of p21Waf1/Cip1 and p27Kip1 expression, and decrease of Cdc25C expression. Moreover, treatment with 100 nM austrobailignan-1 for 48 h resulted in a pronounced release of cytochrome c followed by the activation of caspase-2, -3, and -9, and consequently induced apoptosis. These events were accompanied by the increase of PUMA and Bax, and the decrease of Mcl-1 and Bcl-2. Furthermore, our study also showed that austrobailignan-1 was a topoisomerase 1 inhibitor, as evidenced by a relaxation assay and induction of a DNA damage response signaling pathway, including ATM, and Chk1, Chk2, γH2AX phosphorylated activation. Overall, our results suggest that austrobailignan-1 is a novel DNA damaging agent and displays a topoisomerase I inhibitory activity, causes DNA strand breaks, and consequently induces DNA damage response signaling for cell cycle G2/M arrest and apoptosis in a p53 independent manner.

IMMUNEPOTENT CRP induces cell cycle arrest and caspase-independent regulated cell death in HeLa cells through reactive oxygen species production

“…Here we show that cell cycle was arrested in G2/M phase, and this was observed from 8 h to 48 h of treatment at a 1.25 U/mL concentration. There are several agents, such genistein [ 64 ], austrobailignan-1 [ 65 ], and curcumin analog WZ35 [ 66 ], that can also cause an arrest in the G2/M phase of the cell cycle followed by cell death induction. Although a recent publication of our research group showed that I-CRP does not affect cell cycle in bone marrow cells of mice treated with I-CRP [ 11 ], here we show that in cervical cancer cells it induces cell cycle arrest in G2/M phase, uncovering a different effect in cancer cells.…”

DNA damage‐induced apoptosis and mitogen‐activated protein kinase pathway contribute to the toxicity of dronedarone in hepatic cells

“…Topoisomerase inhibitors have been reported to induce capase-2 mediated DNA damage (Perchellet et al, 2004;Hua et al, 2006;Tomicic and Kaina, 2013;Wu et al, 2015). Topoisomerase inhibitors have been reported to induce capase-2 mediated DNA damage (Perchellet et al, 2004;Hua et al, 2006;Tomicic and Kaina, 2013;Wu et al, 2015).…”

“…DNA damage can also result from topoisomerases dysfunction, which causes single-and double-strand DNA cleavage. Topoisomerase inhibitors have been reported to induce capase-2 mediated DNA damage (Perchellet et al, 2004;Hua et al, 2006;Tomicic and Kaina, 2013;Wu et al, 2015). Therefore, it was of interest to investigate the involvement of topoisomerases in dronedaroneassociated DNA damage.…”

Asymmetric Chemoenzymatic Synthesis of (−)‐Podophyllotoxin and Related Aryltetralin Lignans

“…Several other aryltetralin lignans with alternative substitution patterns on the aryl rings have also been identified in nature (e.g., 3-6). [4] Interestingly,investigations into the bioactivities of these lignans have suggested that subtle changes in the substitution patterns of the aromatic rings could significantly affect the microtubule depolymerizing activity and therapeutic window of the scaffold. [4b,d,e] Them edicinal importance of this natural product family has spurred numerous chemical approaches, [5,6] including arecent Pd-catalyzed C À Harylation strategy to 1 by Maimone and co-workers.…”