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Two new scalarane sesterterpenoids, 12 β -(3′ β -hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al ( 1 ) and 12 β -(3′ β -hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al ( 2 ), along with one known tetraprenyltoluquinol-related metabolite ( 3 ), were isolated from the sponge  Carteriospongia  sp. In leukemia Molt 4 cells,  1  at 0.0625 μg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than  2  and  3 . The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of  3  was supported by the  in vivo  experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound  1  apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis,  1  exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70 S6k , NFκB, Raf-1, p-GSK3β, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of  1 . However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after  1  treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.

scientific reports

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