The fungus-derived compound
cephalochromin, isolated from the fermented broth of Cosmospora vilior YMJ89051501, shows growth-inhibitory and apoptotic activity against human
lung cancer A549 cells in a concentration-dependent manner with an IC50 value of 2.8 μM at 48 h.
Cephalochromin induced cell cycle arrest at the G0/G1 phase through down-regulation of
cyclin D1,
cyclin E, Cdk 2, and Cdk 4 expressions.
Cephalochromin markedly increased the hypodiploid sub-G1 phase (apoptosis) of the cell cycle at 48 h as measured by flow cytometric analysis.
Reactive oxygen species generation and loss of the mitochondrial membrane potential (
MMP) were also markedly induced by
cephalochromin. Moreover, the immunoblotting assays showed that
cephalochromin reduced
survivin and Bcl-xL expression and induced the activation of
caspase-8, -9, and -3 and the cleavage of
poly(ADP-ribose) polymerase, indicating the involvement of a
caspase signaling cascade. The
caspase inhibitor
Z-VAD-fmk significantly suppressed
cephalochromin-induced apoptosis.
Cephalochromin also triggered LC3 II, autophagic marker, expression. Taken together, this is the first report that
cephalochromin induced an antiproliferative effect on human
lung cancer cells through mitochondrial disruption and down-regulation of
survivin, leading to cell cycle arrest at the G0/G1 phase, loss of
MMP, and subsequently apoptotic cell death.