In this study, we investigated whether DHA, a nutritionally important n-3
unsaturated fatty acid, modulated the sensitivity of
brain tumor cells to the anticancer
drug,
etoposide (
VP16).
Medulloblastoma (MB) cell lines, Daoy and D283, and
glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or
VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and
VP16, whereas the two MB cell lines showed high sensitivity. DHA or
VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to
VP16 in the MB cell lines. To understand the mechanisms of combined DHA and
VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and
VP16, in comparison to
VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC,
Survivin, PIK3R1,
MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and
VP16 in
brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that
brain tumors genotypically mimicked by MB cells may benefit from
therapies combining DHA with
VP16.