Journal
CANCER BIOLOGY & THERAPY
Volume 2, Issue 4, Pages 347-353Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.2.4.422
Keywords
mda-7; GST-MDA-7; radiation; necrosis; glioma; GBM; PI3K; AKT; MAPK; P38; JNK; survival
Categories
Funding
- NCI NIH HHS [CA88906] Funding Source: Medline
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Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad. mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad. mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad. mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Ad. mda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G(1) /G(0) and G(2)/M phases of the cell cycle, implying Ad. mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis. Ad. mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad. mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.
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