manumycin and Mesothelioma

Manumycin A (Manu A) 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 Manu A has cancer preventive and chemotherapeutic effects on malignant pleural mesothelioma (MPM) through regulation of Sp1 and induction of mitochondrial cell death pathway. Manu A 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 4.3 µM in the MSTO-311H and H28 cells following 48 h incubation, respectively. Manu A induced a significant increase in apoptotic indices as shown by DAPI staining, Annexin V assay, multi-caspase activity and mitochondrial membrane potential assay. The downregulation of Sp1 mRNA and protein expression by Manu A led to apoptosis by suppressing Sp1-regulated proteins (cyclin D1, Mcl-1 and survivin). Manu A decreased the protein levels of BID, Bcl-xL and PARP while it increased Bax levels. Manu A caused depolarization of the mitochondrial membrane with induction of CHOP, DR4 and DR5. Our results demonstrated that Manu A exerted anticancer effects by inducing apoptosis via inhibition of the Sp1-related signaling pathway in human MPM.

Topics: Annexin A5; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; BH3 Interacting Domain Death Agonist Protein; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Cell Survival; Cyclin D1; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Membrane Potential, Mitochondrial; Mesothelioma; Mesothelioma, Malignant; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Pleural Neoplasms; Poly(ADP-ribose) Polymerases; Polyenes; Polyunsaturated Alkamides; Receptors, TNF-Related Apoptosis-Inducing Ligand; Sp1 Transcription Factor; Survivin; Transcription Factor CHOP