5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity

Abstract

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment.

Marine natural products

“…Further examination of the biological activities of purified soft coral-derived cembranoids has identified antioxidant and cytotoxic properties of sinularin, 571–573 that 5- epi -sinuleptolide is antiproliferative towards pancreatic tumour cells inducing apoptosis and cell cycle arrest 574 and that crassolide, in models related to the autoimmune disease antiphospholipid syndrome, can suppress dendritic cell maturation and downstream T cell responses. 575 Four new examples of briarane-type diterpenoids, 2-butyryloxybriarane B-3 1336 , 9-acetylbriarenolide S 1337 , briarenolide W 1338 and 12-isobriarenolide P 1339 , were isolated from a Yucatan Peninsula collection of Briareum asbestinum .…”

Natural Products of Marine Origin for the Treatment of Colorectal and Pancreatic Cancers: Mechanisms and Potential

“…Sustaining high cyclin B1–CDK1 activity resulted in cell arrest in the M phase and caused cell cycle arrest. 5- epi -sinuleptolide also suppressed the expression of cyclin D, which is an important cell cycle regulator throughout the cell cycle [ 82 ]. Ono et al reported that p53 induced G1/S phase or G2/M arrest via p21 inhibition of CDKs [ 83 ].…”

“…Their results indicated that 5- epi -sinuleptolide induced p21 expression but not p53 expression. Therefore, Tsai et al suggested that 5- epi -sinuleptolide mediates cell cycle arrest through a p53 independent pathway [ 82 ].…”

Discovery and photosynthesis of sinuaustones A and B, diterpenoids with a novel carbon scaffold isolated from soft coral Sinularia australiensis from Hainan

“…The genus Sinularia (order Alcyonacea, family Alcyoniidae), composed of about 150 species, 1 a has long been an intensive research subject of marine natural product chemists and has proved to be a rich source of structurally diverse and biologically active terpenoids. 1 b To our knowledge, till now, more than 700 intriguing sesqui- and diterpenoids, some of which showed a wide range of biological activities, including cytotoxic, 2 anti-inflammatory, 3 immunopotentiation, 4 neuroprotective effects, 5 etc ., have been reported from various species of this genus. The complex structural features of Sinularia terpenoids have attracted much attention from natural product chemists, synthetic chemists and pharmacologists as well.…”