Abstract
Two new scalarane sesterterpenoids, 12β-(3′β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12β-(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, p70S6k, 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.
Highlights
Two new scalarane sesterterpenoids, 12β-(3′β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara16-en-25-al (1) and 12β-(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
There is considerable interest in developing potential Heat shock proteins (Hsp)[90] inhibitors, with a much simpler rationale, through the depletion of oncogenic Hsp[90] clients[6]. The structure of this protein is composed of three major regions: an amino (N)-terminal domain with an adenosine triphosphate (ATP)-binding and hydrolyzing pocket, a middle domain involved in client protein recognition/binding, and a carboxy (C)-terminal domain[7]
We examined the content of EtOAc extract of Carteriospongia (Phyllospongia) sp. which led to the isolation of two new scalarane sesterterpenoids and one known tetraprenyltoluquinol-related metabolite
Summary
12β-(3′β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara16-en-25-al (1) and 12β-(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. Several Hsp[90] inhibitors have entered clinical trials, but none of them has been approved as an anticancer agent[12] Another important group of proteins, topoisomerases (Topo), has attracted attention due to their crucial role in cell survival and replication[13]. Despite the effectiveness of Topo II poisons as anticancer drugs, they can trigger chromosomal breaks leading to secondary leukemogenesis[14,23,24] One solution of this side effect was the development of catalytic Topo II inhibitors such as bisdioxopiperazines which eliminate the essential enzymatic activity of Topo IIα17. The cytotoxic effect of the new scalarane-type sesterterpenoid (1) on human leukemia Molt 4 cells involved induction of ER stress as demonstrated by the increase in ROS generation as well as ATF 6 cleavage and Chop expression. The treatment of Molt 4 cells with compound 1 suppressed client protein expression and accumulation of Hsp[70] in the cytosolic compartment and well as reduced the transcription factors (HSF 1 and HIF 1) expression as demonstrated by Western blot and immunofluorescent analyses
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