Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway

Marine Drugs

Jui-Hsin Su⁵  Yu-Cheng Chen⁵  Mohamed El-Shazly¹  Ying-Chi Du¹  Chiang-Wen Su³  Chia-Wei Tsao⁵  Li-Lian Liu²  Yalan Chou²  Wen-Been Chang⁵  Yin-Di Su⁵  Michael Y. Chiang⁶  Yao-Tsung Yeh⁴ 

[1] Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan; E-Mails:;Institute of Marine Biology, National Sun Yat-sen University, Kaohsiung, Taiwan; E-Mails:;Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, Taiwan; E-Mail:;Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 831, Taiwan; E-Mail:;National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan; E-Mails:;Department of Chemistry, National Sun Yat-sen University, Kaohsiung 804, Taiwan; E-Mail:

关键词: apoptosis;    dibromotyrosine;    mitochondrial dysfunction;    oxidative stress;    topoisomerase;   

DOI  :  10.3390/md11093168

来源: mdpi

【 摘 要 】

A dibromotyrosine derivative, (1′R,5′S,6′S)-2-(3′,5′-dibromo-1′,6′-dihydroxy-4′-oxocyclohex-2′-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl-cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFκB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFκB pathway.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.