Flavopiridol is a
flavone that inhibits several
cyclin-dependent kinases and exhibits potent growth-inhibitory activity against a number of human tumor cell lines, both in vitro and when grown as xenografts in mice. It is presently being investigated as a novel
antineoplastic agent in the primary screen conducted by the Developmental
Therapeutics Program, National Cancer Institute. Because
breast cancer is the most common
cancer and second leading cause of
cancer-related deaths in women in the United States, we investigated whether
flavopiridol could be an effective agent against a series of isogenic
breast- cancer cell lines having different levels of erbB-2 expression and differential invasion and metastatic characteristics.
Flavopiridol was found to inhibit the growth of MDA-MB-435 (parental) and 435.eB (stable transfectants) cells that were established by transfecting c-erbB-2
cDNA into MDA-MB-435. Induction of apoptosis was also observed in these cell lines when treated with
flavopiridol, as measured by
DNA laddering, PARP, and CPP32 cleavages. We also found modest up-regulation of Bax and down-regulation of Bcl-2, but there was a significant down-regulation of c-erbB-2 in
flavopiridol-treated cells.
Gelatin zymography showed that
flavopiridol inhibits the secretion of
matrix metalloproteinase (
MMP;
MMPs 2 and 9) in the
breast cancer cells and that the inhibition of c-erbB-2 and
MMPs may be responsible for the inhibition of cell invasion observed in
flavopiridol-treated cells. Collectively, these molecular effects of
flavopiridol, however, were found to be independent of c-erbB-2 overexpression, suggesting that
flavopiridol may be effective in all
breast cancer. From these results, we conclude that
flavopiridol inhibits the growth of MDA-MB-435
breast cancer cells, induces apoptosis, regulates the expression of genes, and inhibits invasion and, thus, may inhibit
metastasis of
breast cancer cells. These findings suggest that
flavopiridol may be an effective chemotherapeutic or preventive agent against
breast cancer.