VorinostatSAHAPromotes Hyper-Radiosensitivity in Wild Type p53 Human Glioblastoma Cells.
Glioblastoma multiforme (GBM) is a very aggressive and locally invasive tumor. The current standard of care is partial brain radiation therapy (60 Gy) concurrently with the alkylating agent temozolomide (TMZ). However, patients' survival remains poor (6-12 months) mainly due to local and diffuse (distant) recurrence. The possibility to promote hyper radiosensitivity (HRS) with low dose radiation may contribute to improve outcome. Here, we evaluated the effect of VorinostatSAHAand TMZ on glioblastoma cells' sensitivity to low dose radiation. Clonogenic survivals were performed on D54 (p53 and PTEN wild type) and U118 (p53 and PTEN mutants) cells exposed to clinically relevant doses of VorinostatSAHAand TMZ and increasing radiation doses. Apoptosis was measured by the activation of caspase-3 and the role of p53 and PTEN were evaluated with the p53 inhibitor pifithrin α and the PI3K/AKT pathway inhibitor LY29002. VorinostatSAHApromoted HRS at doses as low as 0.25 Gy in the D54 but not the U118 cells. Killing efficiency was associated with caspase-3 activation, delayed H2AX phosphorylation and abrogation of a radiation -induced G2 arrest. Inhibiting p53 function with pifithrin α prevented the promotion of HRS by VorinostatSAHA. Moreover, LY29002, a PI-3K inhibitor, restored promotion of HRS by VorinostatSAHAin the p53 mutant U118 cells to levels similar to the p53 wild type cells. TMZ also promoted HRS at doses as low as 0.15 Gy. These finding indicate that HRS can be promoted in p53 wild type glioblastoma cells through a functional PTEN to delay DNA repair and sensitize cells to low dose radiation. Promotion of HRS thus appears to be a viable approach for GBM that could be used as a basis to develop new Phase I/II studies.
Eric
E
Diss
NarasimhaRao
N
Nalabothula
Duc
D
Nguyen
Elizabeth
E
Chang
Young
Y
Kwok
France
F
Carrier
Glioblastoma; HDACI; Low dose fractionated radiation; p53; PTEN