Discovery And Study Of Anti-glioma Constituents From Marine Bacteria

Gliomas are the most common and high death malignant brain tumors and locate at many important brain function areas,which make the surgical resection extremely difficult.Therefore,chemotherapy has played a more important role in the treatment and prevention of gliomas.The first generation of anti-glioma drugs and temozolomide(TMZ),the only drug that has been independently used for the treatment of gliomas,are cytotoxicity-based alkylating agents with serious side effects and drug resistance.Therefore,there is an urgent need to discover new anti-glioma drugs with novel mechanism of action.The secondary metabolites from marine microorganisms are important sources for discovery of anti-glioma lead compounds.In this study,a total of 255 marine bacteria strains were isolated from samples of marine origin,of which 27 strains' cultures were found to be active against the cell viability of gliomas.The chemical ingredients and their anti-glioma activity of five actinomycetes of Streptomyces fradiae PTZ0025,Streptomyces sp.P11-23B,Pseudonocardia sp.HS7,Streptomyces sp.Q24,and Streptomyces sp.P83B were investigated.By using various column chromatography and HPLC,a total of 23 compounds were isolated from the five actinomycetes and their structures were determined by a combination of various NMR spectra,HRESIMS and MS-MS data,and chemical degradation.Eight compounds have been found to be new compounds,including fradimycin A(2),fradimycin B(3),fradic acid A(5),fradic acid B(6),streptodepsipeptide P11A(8),streptodepsipeptide P11B(9),curvularin-7-O-a-D-glucopyranoside(12),and 3-acetylamino-N-2-thienyl-propanamide(15).Anti-glioma assay indicated that 18 of 23 isolated compounds were found to have activity in inhibiting the proliferation of glioma cells.It has been found that the anti-glioma compounds 7,8,12,13,21,and 22 remarkably reduced the protein expression levels of different metabolic enzymes in U87-MG cells.Interestingly,these six compounds were isolated from the cultures of three actinomycetes of Streptomyces sp.P11-23B,Pseudonocardia sp.HS7,and Streptomyces sp.P83B,respectively;while the cultures from these three actinomycetes had the activity to reduce glucose consumption and lactate production.The data suggested the significance and application prospect of the discovery of targeted bioactive compounds based on the effects of cultures from bacteria on cell viability and glucose consumption and lactate production in glioma cells.This study demonstrated that streptodepsipeptide P11A(8)had potent activity against glioma cells and low cytotoxicity to normal human astrocytes,induced apoptosis in U87-MG cells,and arrested cell cycle at the G0/G1 phase in glioma U87-MG and U251 cells.Compound 8 also reduced the production of lactate,selectively downregulated the protein expression levels of multiple enzymes of different metabolic pathways in U87-MG cells,and converted glioma cell metabolism to oxidative phosphorylation,which is a predominant metabolic process of glucose in normal cells.Therefore,streptodepsipeptide P11A(8)has a potential for further investigation as an anticancer lead compound.