Docosahexaenoic acid (DHA) sensitizes brain tumor cells to etoposide-induced apoptosis
1Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
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.
Insights
Docosahexaenoic acid (DHA) enhances brain tumor cell sensitivity to etoposide (VP16). This combination therapy, particularly for medulloblastoma, shows promise by downregulating DNA repair and survival pathways.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Pharmacology
Background:
- Brain tumors, including medulloblastoma (MB) and glioblastoma (GBM), present significant therapeutic challenges.
- Etoposide (VP16) is a standard chemotherapeutic agent, but resistance can limit its efficacy.
- Docosahexaenoic acid (DHA), an omega-3 fatty acid, has potential anticancer properties.
Purpose of the Study:
- To investigate if DHA modulates the sensitivity of brain tumor cells to etoposide (VP16).
- To explore the underlying molecular mechanisms of combined DHA and VP16 treatment in MB cells.
Main Methods:
- Medulloblastoma (Daoy, D283) and glioblastoma (U138, U87) cell lines were treated with DHA, VP16, or both.
- Cell proliferation and apoptosis were assessed using MTS assays and Hoechst 33342/PI staining.
- Pathway-specific oligo array analysis was employed to examine gene expression changes.
Main Results:
- MB cell lines (Daoy, D283) exhibited increased sensitivity to VP16 when pretreated with DHA, unlike GBM cell lines.
- Combined DHA and VP16 treatment significantly suppressed genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis.
- Key suppressed genes included PRKDC, Survivin, PIK3R1, MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1.
Conclusions:
- DHA enhances VP16 efficacy in specific brain tumor models (MB) by downregulating critical survival and repair pathways.
- The combination therapy's effects are partly mediated through the PI3K/MAPK signaling pathways.
- Therapeutic strategies combining DHA with VP16 may offer benefits for brain tumors similar to MB.