Libertellenone H, a Natural Pimarane Diterpenoid, Inhibits Thioredoxin System and Induces ROS-Mediated Apoptosis in Human Pancreatic Cancer Cells

• Main Authors: Weirui Zhang, Yuping Zhu, Haobing Yu, Xiaoyu Liu, Binghua Jiao, Xiaoling Lu
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: Molecules
• Subjects: Libertellenone H; pancreatic cancer; ROS; Trx system; apoptosis
• Online Access: https://www.mdpi.com/1420-3049/26/2/315
• ISSN: 1420-3049

Libertellenone H (LH), a marine-derived pimarane diterpenoid isolated from arctic fungus <i>Eutypella</i> sp. D-1, has shown effective cytotoxicity on a range of cancer cells. The present study is to explore the anticancer effect of LH on human pancreatic cancer cells and to investigate the intracellular molecular target and underlying mechanism. As shown, LH exhibited anticancer activity in human pancreatic cancer cells by promoting cell apoptosis. Mechanistic studies suggested that LH-induced reactive oxygen species (ROS) accumulation was responsible for apoptosis as antioxidant N-acetylcysteine (NAC) and antioxidant enzyme superoxide dismutase (SOD) antagonized the inhibitory effect of LH. Zymologic testing demonstrated that LH inhibited Trx system but had little effect on the glutathione reductase and glutaredoxin. Mass spectrometry (MS) analysis revealed that the mechanism of action was based on the direct conjugation of LH to the Cys³²/Cys³⁵ residue of Trx1 and Sec⁴⁹⁸ of TrxR, leading to a decrease in the cellular level of glutathione (GSH) and activation of downstream ASK1/JNK signaling pathway. Taken together, our findings revealed LH was a marine derived inhibitor of Trx system and an anticancer candidate.