FK228 augmented temozolomide sensitivity in human glioma cells by blocking PI3K/AKT/mTOR signal pathways
2016
Abstract
Temozolomideis a novel cytotoxic agent currently used as first-line chemotherapy for glioblastoma multiforme (GBM).
Romidepsin(FK228), a
histone deacetylase inhibitor, is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, combination of the two drugs in
gliomaremains largely unknown. In the present study, we evaluated the combinatory effects of FK228 with TMZ in
glioma, and its molecular mechanisms responsible for these effects.
Gliomacell lines were treated with TMZ, FK228 or the combination of drugs. The resistance effect including cytotoxicity and apoptosis was determined in
gliomacells, respectively. We further evaluated the effects of FK228 in the PI3K/Akt-signaling pathway in vitro . Mice engrafted with 5 × 10 6 LN382 cells were treated with TMZ, FK228 or the combination of two drugs, and tumor weights and volumes were measured, respectively. FK228 enhanced the cytotoxic effects of TMZ in
gliomacells compared to vehicle-treated controls or each drug alone. The combination of FK228 and TMZ-induced apoptosis was demonstrated by increased expression of cleaved-Caspase 3, Bax, cleaved-PARP, and decreased Bcl-2 expression. Furthermore, the expression of key components of the PI3K/Akt-signaling pathway showed that combination of FK228 and TMZ block PI3K/Akt pathways in vitro. This
block effectwas also confirmed in vivo in mice models. Mice treated with both FK228 and TMZ drugs showed significantly reduced tumor weights and volumes, compared to each drug alone. Our results suggested that FK228 augmented
temozolomidesensitivity in human
gliomacells partially by blocking PI3K/AKT/
mTOR signal pathways. It thus may provide a promising target for improving the therapeutic outcome of TMZ-resistant
gliomas, although further studies will be needed.
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