Docosahexaenoic Acid (DHA) Sensitizes Brain Tumor Cells to Etoposide-Induced Apoptosis

Abstract

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.

Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis

“…We made similar observations: 25-75 μM DHA diminished the proliferation rate and altered the metabolism of U87 MG cells (Figure 2). DHA treatment had a distinct effect on medulloblastoma (DAOY and D283) cells compared to glioma cells (U87 MG and U138) regarding cell proliferation: it did not affect glioma cells, while it inhibited proliferation of medulloblastoma cells [29]. …”

The Caveolin-1 Connection to Cell Death and Survival

“…Many of these interactions, such as those with the epidermal growth factor receptor, Src kinases, the Ras/Raf/MAPK pathway, PKCs and endothelial nitric oxide synthase (eNOS), occur via the scaffolding domain of Caveolin-1 (CSD; amino acids [82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101] and the scaffolding domain binding domain (CBD) found in the respective target proteins [3]. However, as highlighted in Fig.…”

“…More recently, work from our group has shown that expression of the Inhibitor of Apoptosis (IAP) protein Survivin and also cyclooxygenase-2 (COX-2) are down-regulated by Caveolin-1 in a -catenin-Tcf/Lefdependent manner [81][82]. Interestingly, reduction of survivin expression has been associated with enhanced sensitivity to anti-cancer drugs [84].…”

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

“…Wang et al combined the use of DHA with the anticancer drug etoposide (VP16) to induce apoptosis in medulloblastoma cell lines, Daoy and D283, and glioblastoma cell lines, U87 and U138. 44 U87 and U138 cell lines were insensitive to pretreatment with DHA followed by VP16 administration, whereas Daoy and D283 cells showed little responsiveness to either treatment alone, but a significant induction of apoptosis was observed with the combination. Wang's evidence suggests that the apoptosis mechanism involves the downregulation of survival pathways associated with DNA repair and PI3K/MAPK.…”