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.