The therapeutic effects of Longikaurin A, a natural ent-kauranoid, in esophageal squamous cell carcinoma depend on ROS accumulation and JNK/p38 MAPK activation

• Published in: Toxicology letters Vol. 280; pp. 106 - 115
• Main Authors: Che, Yun, Wang, Jingnan, Yuan, Zuyang, Li, Yuan, Lu, Zhiliang, Zhang, Zhirong, Zhang, Jinyao, Wan, Jun, Sun, Handong, Chen, Zhaoli, Pu, Jianxin, He, Jie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.10.2017
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Diterpenes, Kaurane - pharmacology; Enzyme Activation - drug effects; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal squamous cell carcinoma; G2/M cell cycle arrest; Gene Expression Regulation, Neoplastic - drug effects; Humans; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; Longikaurin A; MAPK pathways; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Bcl-2; Reactive oxygen species; JNK; H&E; MAPK pathways; MAPK; PVDF; ESCC; Longikaurin A; SB; LK-A; NAC; NIH-3T3; ROS; HEK-293; Esophageal squamous cell carcinoma; SP; ERK; G2/M cell cycle arrest; Apoptosis
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2017.08.005

[Display omitted] •LK-A inhibits ESCC cells viability and induces G2/M cell cycle arrest.•LK-A induces ROS production and apoptosis in ESCC cells.•The JNK/p38 MAPK pathways are linked to ROS in LK-A-induced apoptosis in ESCC cells.•The manuscript suggests that LK-A has potential as a treatment for ESCC. Effective treatments for esophageal squamous cell carcinoma (ESCC), one of the most common cancers in China, are lacking. Longikaurin A (LK-A), an ent-kauranoid diterpenoid isolated from Isodon ternifolius, has been shown to have potent cytotoxic effects on ESCC cells both in vivo and in vitro, mainly by inducing apoptosis. In this study, LK-A inhibited ESCC cells viability and induced G2/M cell cycle arrest. Moreover, LK-A was also highly effective in a KYSE-30 xenograft nude mouse model. Treatment with Z-VAD(OMe)-FMK partially attenuated LK-A-induced apoptosis. LK-A significantly induced reactive oxygen species (ROS) production in ESCC cells, and LK-A-induced apoptosis was attenuated by the ROS scavenger N-acetyl cysteine (NAC). Furthermore, we found that treatment with LK-A activated both the JNK and p38 MAPK signaling pathways, resulting in increases in ROS levels and apoptosis induction. Taken together, these findings indicate that LK-A exerts novel anti-tumor effects in ESCC cells by activating the JNK and p38 MAPK pathways and inducing increases in ROS production, which suggest that the compound may have potential as a clinical therapeutic agent.