Abstract
ManumycinA (ManuA) is a natural product isolated from Streptomyces parvulus and has been reported to have anti-carcinogenic and anti-biotic properties. However, neither its molecular mechanism nor its molecular targets are well understood. Thus, the aim of the present study was to explore the possibility that ManuA has cancer preventive and chemotherapeutic effects on malignant pleural mesothelioma (MPM) through regulation of Sp1 and induction of mitochondrial cell death pathway. ManuA inhibited the cell viability of MSTO-211H and H28 cells in a concentration‑dependent manner as determined by MTS assay. IC50 values were calculated as 8.3 and 4.3µM in the MSTO-311H and H28 cells following 48h incubation, respectively. ManuA induced a significant increase in apoptotic indices as shown by DAPI staining, AnnexinV assay, multi-caspase activity and mitochondrial membrane potential assay. The downregulation of Sp1 mRNA and protein expression by ManuA led to apoptosis by suppressing Sp1-regulated proteins (cyclinD1, Mcl-1 and survivin). ManuA decreased the protein levels of BID, Bcl-xL and PARP while it increased Bax levels. ManuA caused depolarization of the mitochondrial membrane with induction of CHOP, DR4 and DR5. Our results demonstrated that ManuA exerted anticancer effects by inducing apoptosis via inhibition of the Sp1-related signaling pathway in human MPM.
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