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.
Highlights
Malignancies are one of the most serious diseases that damage human health in the modern world. the efficacy of chemotherapy for the majority of cancer types has improved over the last three decades, the high toxic effects of chemotherapeutic drugs, causing a severe reduction in quality of life, are still formidable problems in clinical medicine [1]
The results showed that the viability of A375 cells by dicitrinone B presented a slightly lower change compared to the cells treated with ten times the concentration of 5-Fu after 12 h of treatment; when the exposure time reached 24 h, the viability of cells treated with 20 μM and 40 μM of dicitrinone B was more significantly decreased compared to that of cells treated with ten times the concentration of 5-Fu, and it dropped to 36.17% and 8.16%, respectively; the viability for 48 h under dicitrinone B treatment presented slightly lower growth than did the 24-h group and still presented a stronger effect compared to
We found that pro-PARP decreased and cleaved-PARP increased both in a dose-dependent manner, indicating that PARP was cleaved during the process of apoptosis induced by dicitrinone B
Summary
The efficacy of chemotherapy for the majority of cancer types has improved over the last three decades, the high toxic effects of chemotherapeutic drugs, causing a severe reduction in quality of life, are still formidable problems in clinical medicine [1]. Many researchers have begun to investigate natural products, due to their antitumor activities and low side-effects [2]. Natural products from microbes have been a remarkable source of antitumor agents [3], in view of their advantages, such as fast growth and easy culture and purification. Since the discovery of antinomycin around 1940, many microbial products have been approved as antitumor drugs, including actinomycin d, anthracyclines, bleomycin, mitomycin c, anthracenones, enediynes and epothilones. Like the utilization of uncultivated microorganisms and metagenomics, have exhibited great promise for discovering new and powerful antitumor drugs [3]
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