title: Apoptosis induced by desmethyl-lasiodiplodin is associated with upregulation of apoptotic genes and downregulation of monocyte chemotactic protein-3.
abstract: There is growing interest in the discovery of bioactive metabolites from endophytes as an alternative source of therapeutics. Identification of their therapeutic targets is essential in understanding the underlying mechanisms and enhancing the resultant therapeutic effects. As such, bioactive compounds produced by endophytic fungi from plants at the National Park, Pahang, Malaysia, were investigated. Five known compounds were identified using LC-UV-MS-NMR and they include trichodermol, 7-epi-brefeldin A, (3R,4S)-4-hydroxymellein, desmethyl-lasiodiplodin and cytochalasin D. The present study went on to investigate the potential anticancer effects of these compounds and the corresponding molecular mechanisms of the lead compound against human breast adenocarcinoma, MCF-7. For the preliminary screening, the cytotoxicity and apoptotic effects of these compounds against MCF-7 were examined. The compounds were also tested against noncarcinogenic hepatocytes (WRL68). The differential cytotoxicity was then determined using the MTT assay. Desmethyl-lasiodiplodin was found to suppress the growth of MCF-7, yielding an inhibitory concentration (IC50) that was seven-fold lower than that of the normal cells. The cytotoxic effect of desmethyl-lasiodiplodin was accompanied by apoptosis. Subsequent analysis demonstrated increased expression levels of caspase 3, c-myc and p53. Further, desmethyl-lasiodiplodin resulted in inhibition of monocyte chemotactic protein (MCP)-3, a cytokine involved in cell survival and metastasis. Hence, this study proposed that desmethyl-lasiodiplodin inhibited growth and survival of MCF-7 through the induction of apoptosis. This anticancer effect is mediated, in part, by upregulation of apoptotic genes and downregulation of MCP-3. As desmethyl-lasiodiplodin elicited minimal impact against normal hepatocytes, our findings also imply its potential use as a specific apoptotic agent in breast cancer treatment.
authors.affiliation: Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Selangor Darul Ehsan, Malaysia.
authors.forename: Nurul Aqmar M N
authors.initials: NA
authors.lastname: Hazalin
authors.forename: Siong Meng
authors.initials: SM
authors.lastname: Lim
authors.forename: Anthony L J
authors.initials: AL
authors.lastname: Cole
authors.forename: Abu Bakar A
authors.initials: AB
authors.lastname: Majeed
authors.forename: Kalavathy
authors.initials: K
authors.lastname: Ramasamy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D060026:Endophytes / Q000737:chemistry; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D009183:Mycotoxins / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C515450:CCL7 protein, human; D054410:Chemokine CCL7; C489427:MYC protein, human; D009183:Mycotoxins; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C584013:desmethyl-lasiodiplodin; D015025:Zearalenone; C505407:CASP3 protein, human; D053148:Caspase 3