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

Abstract

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.

Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

“…The externalization of phosphatidylserine (PS) and membrane integrity were quantified using an annexin V- FITC staining kit72. In brief, 10 6 cells were grown in 35 mm diameter plates and were labeled with annexin V-FITC (10 μg/mL) and PI (20 μg/mL) prior to harvesting.…”

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…bisacetylenic alcohol ( 191 ) [184]; conicasterol E ( 192 ) [185]; 6”-debromohamacanthin A ( 193 ) [186]; dieckol ( 194 ) [187]; fructigenine A ( 195 ) [188]; geoditin A ( 196 ) [189]; gorgosterol ( 197 ) [190]; gracilioether B ( 198 ) [191]; gracilioether K ( 199 ) [192]; herdmanine K ( 200 ) [193]; hyrtioreticulin A ( 201 ) [194]; new Kunitz-type protease inhibitor InHVJ ( 202 ) [195]; jaspamide ( 203 ) [196]; latonduine A ( 204 ) [197]; leucettine L41 ( 205 ) [169]; manzamine A ( 206 ) [198]; nahuoic acid A ( 207 ) [199]; namalide ( 208 ) [200]; ningalins C and D ( 209 , 210 ) [201]; octaphlorethol A ( 114 ) [120]; petrosaspongiolide M ( 211 ) [202]; petrosiol A ( 212 ) [203]; phidianidine A ( 213 ) [204]; Poly-APS ( 214 ) [205]; Pseudoceratina sp. dibromotyrosine ( 215 ) [206]; pseudopterosin A ( 216 ) [207]; sargachromanol G ( 217 ) [208]; S. graminifolium polysaccharide ( 218 ) [209]; S. patens phloroglucinol ( 219 ) [210]; S. xiamenensis benzopyran ( 220 ) [211]; theonellasterol ( 221 ) [212]; toluquinol ( 222 ) [213]; and U. lactuca fatty acid ( 223 ) [214]. …”

New Antimicrobial Bromotyrosine Analogues from the Sponge Pseudoceratina purpurea and Its Predator Tylodina corticalis

“…Sponges of the order Verongida are unique in the Demospongiae as the only group that contains alkaloids derived from bromotyrosine and sterols of the aplystane type; these are distinct chemotaxonomic markers for all the verongid genera [ 1 , 2 , 3 ]. The alkaloids have been reported to have antimicrobial [ 4 , 5 , 6 , 7 ], antifungal [ 8 , 9 ], cytotoxic [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], and antimalarial [ 22 , 23 , 24 ] activity for example and many have unique modes of action. Consequently, verongid sponges have no natural predators other than a few specialised molluscs such as nudibranchs [ 25 ].…”