Anticancer activity of isoobtusilactone A from Cinnamomum kotoense: involvement of apoptosis, cell-cycle dysregulation, mitochondria regulation, and reactive oxygen species.
In this study, we investigate the anticancer effect of isoobtusilactone A (IOA), a constituent isolated from the leaves of Cinnamomum kotoense, on human non-small cell lung cancer (NSCLC) A549 cells. IOA was found to induce the arrest of G2-M phase, induce apoptosis, increase sub-G1, and inhibit the growth of these cells. Further investigation revealed that IOA's blockade of the cell cycle was associated with increased levels of p21/WAF1, p27 (kip1), and p53. In addition, IOA triggered the mitochondrial apoptotic pathway, as indicated by an increase in Bax/Bcl-2 ratios, resulting in a loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of PARP. We also found the generation of reactive oxygen species (ROS) to be a critical mediator in IOA-induced inhibition of A549 cell growth. In antioxidant and NO inhibitor studies, we found that by pretreating A549 cells with either N-acetylcystenine (NAC), catalase, mannitol, dexamethasone, trolox, or L-NAME we could significantly decrease IOA production of ROS. Moreover, using NAC to block ROS, we could significantly suppress IOA-induced antiproliferation, antimigration, and anti-invasion. Finally, we found that IOA inhibited the migration and invasion of A549 cell migration and invasion. Taken together, these results suggest that IOA has anticancer effects on A549 cells.
Chen
Chung-Yi
CY
School of Medicine and Health Sciences, Fooyin UniVersity, Kaohsiung County 831, Taiwan, Republic of China.
Chen
Ching-Hsein
CH
Lo
Yi-Ching
YC
Wu
Bin-Nan
BN
Wang
Hui-Min
HM
Lo
Wen-Li
WL
Yen
Chuan-Min
CM
Lin
Rong-Jyh
RJ
D000473:Alkanes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000032:analysis / Q000378:metabolism; D053453:Caspase 9 / Q000032:analysis / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D027424:Cinnamomum / Q000737:chemistry*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis / Q000378:metabolism; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D018515:Plant Leaves / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000737:chemistry; D013624:Taiwan; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism
D000473:Alkanes; D000972:Antineoplastic Agents, Phytogenic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007783:Lactones; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C521340:isoobtusilactone A; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9