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Mar. Drugs 2014, 12(4), 1939-1958; doi:10.3390/md12041939

The Marine Fungal Metabolite, Dicitrinone B, Induces A375 Cell Apoptosis through the ROS-Related Caspase Pathway

1
Institute of Biomedical and Pharmaceutical Technology, College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou 350002, China
2
Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Provincial Tumor Hospital, Fuzhou 350014, China
3
Institute of Biomedical Engineering, Chinese Academy of Medical Science, Peking Union Medical College, Tianjin 300192, China
*
Authors to whom correspondence should be addressed.
Received: 28 January 2014 / Revised: 11 March 2014 / Accepted: 18 March 2014 / Published: 2 April 2014
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Abstract

Dicitrinone B, a rare carbon-bridged citrinin dimer, was isolated from the marine-derived fungus, Penicillium citrinum. It was reported to have antitumor effects on tumor cells previously; however, the details of the mechanism remain unclear. In this study, we found that dicitrinone B inhibited the proliferation of multiple tumor types. Among them, the human malignant melanoma cell, A375, was confirmed to be the most sensitive. Morphologic evaluation, cell cycle arrest and apoptosis rate analysis results showed that dicitrinone B significantly induced A375 cell apoptosis. Subsequent observation of reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) reduction revealed that the apoptosis induced by dicitrinone B may be triggered by over-producing ROS. Further studies indicated that the apoptosis was associated with both intrinsic and extrinsic apoptosis pathways under the regulation of Bcl-2 family proteins. Caspase-9, caspase-8 and caspase-3 were activated during the process, leading to PARP cleavage. The pan-caspase inhibitor, Z-VAD-FMK, could reverse dicitrinone B-induced apoptosis, suggesting that it is a caspase-dependent pathway. Our data for the first time showed that dicitrinone B inhibits the proliferation of tumor cells by inducing cell apoptosis. Moreover, compared with the first-line chemotherapy drug, 5-fluorouracil (5-Fu), dicitrinone B showed much more potent anticancer efficacy, suggesting that it might serve as a potential antitumor agent.
Keywords: dicitrinone B; marine-derived fungus; human malignant melanoma cell A375; anticancer activity; apoptosis dicitrinone B; marine-derived fungus; human malignant melanoma cell A375; anticancer activity; apoptosis
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Chen, L.; Gong, M.-W.; Peng, Z.-F.; Zhou, T.; Ying, M.-G.; Zheng, Q.-H.; Liu, Q.-Y.; Zhang, Q.-Q. The Marine Fungal Metabolite, Dicitrinone B, Induces A375 Cell Apoptosis through the ROS-Related Caspase Pathway. Mar. Drugs 2014, 12, 1939-1958.

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