Sangivamycin has shown a potent antiproliferative activity against a variety of human
cancers. However, little is known about the mechanism of action underlying its antitumor activity. Here we demonstrate that
sangivamycin has differential antitumor effects in
drug-sensitive MCF7/wild type (WT) cells, causing growth arrest, and in multidrug-resistant MCF7/
adriamycin-resistant (ADR) human
breast carcinoma cells, causing massive apoptotic cell death. Comparisons between the effects of
sangivamycin on these two cell lines allowed us to identify the mechanism underlying the apoptotic antitumor effect. Fluorescence-activated cell sorter analysis indicated that
sangivamycin induced cell cycle arrest in the G(2)/M phase in MCF7/ADR cells. A marked induction of c-Jun expression as well as phosphorylation of c-Jun and JNK was observed after
sangivamycin treatment of MCF7/ADR cells but not MCF7/WT cells.
Sangivamycin also induced cleavage of
lamin A and
poly(ADP-ribose) polymerase (PARP) in MCF7/ADR cells, probably via activation of
caspase-6, -7, and -9. Pretreatment with a caspase-9-specific inhibitor or pan-
caspase inhibitor abolished
sangivamycin-induced cleavage of
lamin A and PARP but not
sangivamycin induction of c-Jun expression and phosphorylation. Pretreatment of MCF7/ADR cells with
SP600125, a specific inhibitor of JNK, or with
rottlerin, a specific inhibitor of
protein kinase Cdelta (PKCdelta), significantly reduced the
sangivamycin-induced apoptosis and almost completely abolished
sangivamycin-induced phosphorylation of c-Jun and cleavage of
lamin A and PARP. Transfection of MCF7/ADR cells with PKCdelta small interfering RNAs or PKCdelta antibody or
rottlerin pretreatment significantly suppressed the phosphorylation of JNK. Taken together, our data suggest that
sangivamycin induces mitochondria-mediated apoptotic cell death of MCF7/ADR cells via activation of JNK in a
protein kinase Cdelta-dependent manner.