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Valproic acid promotes radiosensitization in meningioma stem-like cells.

Chiou HY, Lai WK, Huang LC, Huang SM, Chueh SH, Ma HI, Hueng DY - Oncotarget (2015)

Bottom Line: Anchorage-independent growth (AIG) was reduced by VPA.AIG was further reduced by combined treatment with irradiation.Oct4 was further decreased by combined treatment with irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.

ABSTRACT
Although meningioma stem-like cells have been isolated and characterized, their therapeutic targeting remains a challenge. Meningioma sphere cells (MgSCs) with cancer stem cells properties show chemo- and radioresistance in comparison with meningioma adherent cells (MgACs). We tested the effect of valproic acid (VPA), a commonly used anti-epileptic drug, which passes the blood brain barrier, on cultured MgSCs. VPA reduced the viability of MgSCs and MgACs. In MgSCs, treatment with VPA increased radio-sensitivity, expression of p-cdc2, p-H2AX and cleaved caspase-3 and PARP. Anchorage-independent growth (AIG) was reduced by VPA. AIG was further reduced by combined treatment with irradiation. Expression of a stem cell marker, Oct4, was reduced by VPA. Oct4 was further decreased by combined treatment with irradiation. These results suggest that VPA may be a potential treatment for meningioma through targeting meningioma stem-like cells.

No MeSH data available.


Related in: MedlinePlus

Effects of VPA and irradiation on cell viability and on cell cycle, apoptotic, and DNA damaging protein expressions in MgSCsMgSCs were treated with or without 2 mM VPA for 24 h followed by irradiation. (A) 24 h after irradiation, the cell viabilities were determined by MTS assay. Immuno-blots showed the (B) protein expressions of p-cdc2, (C) cleavage of caspase-3 and PARP, and (D) expression of p-H2AX of MgSCs treated with VPA and irradiation. α-actinin, loading control. The quantification results are shown in the right panel. Bars, mean±SEM; *p < 0.05, **p < 0.01, and #p < 0.001 showed significant differences. Data are representative of 3 independent experiments.
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Figure 3: Effects of VPA and irradiation on cell viability and on cell cycle, apoptotic, and DNA damaging protein expressions in MgSCsMgSCs were treated with or without 2 mM VPA for 24 h followed by irradiation. (A) 24 h after irradiation, the cell viabilities were determined by MTS assay. Immuno-blots showed the (B) protein expressions of p-cdc2, (C) cleavage of caspase-3 and PARP, and (D) expression of p-H2AX of MgSCs treated with VPA and irradiation. α-actinin, loading control. The quantification results are shown in the right panel. Bars, mean±SEM; *p < 0.05, **p < 0.01, and #p < 0.001 showed significant differences. Data are representative of 3 independent experiments.

Mentions: Despite the chemoresistance of MgSCs to vincristine [3], VPA induced more severe cell death in MgSCs than in MgACs (Figure 2). The MgSCs were treated with an IC50 dose of VPA (2 mM) and irradiation (5Gy) alone or in combination, and were subjected to MTS assay. The results revealed that MgSCs pre-treated with VPA had reduced cell viability with the use of irradiation compared to the untreated control (p < 0.01) (Figure 3A), indicating that VPA increased the radio-sensitivity of MgSCs. Moreover, p-cdc2 (Tyr15), which was elevated in the G2/M phase of the cell cycle [21], was significantly induced by the combined treatment, compared to the untreated control (p < 0.01) (Figure 3B). The cleavage of apoptotic proteins, caspase-3 and PARP was also induced by the combined treatment (Figure 3C). DNA damage-inducing p-H2AX [22] was also significantly induced by the combined treatment, compared to the untreated control (p < 0.001) (Figure 3D). These findings indicate that VPA enhanced the radiosensitivity of MgSCs and that combined treatment decreased MgSCs survival through mechanisms like cell cycle arrest, apoptosis and DNA fragmentation.


Valproic acid promotes radiosensitization in meningioma stem-like cells.

Chiou HY, Lai WK, Huang LC, Huang SM, Chueh SH, Ma HI, Hueng DY - Oncotarget (2015)

Effects of VPA and irradiation on cell viability and on cell cycle, apoptotic, and DNA damaging protein expressions in MgSCsMgSCs were treated with or without 2 mM VPA for 24 h followed by irradiation. (A) 24 h after irradiation, the cell viabilities were determined by MTS assay. Immuno-blots showed the (B) protein expressions of p-cdc2, (C) cleavage of caspase-3 and PARP, and (D) expression of p-H2AX of MgSCs treated with VPA and irradiation. α-actinin, loading control. The quantification results are shown in the right panel. Bars, mean±SEM; *p < 0.05, **p < 0.01, and #p < 0.001 showed significant differences. Data are representative of 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496410&req=5

Figure 3: Effects of VPA and irradiation on cell viability and on cell cycle, apoptotic, and DNA damaging protein expressions in MgSCsMgSCs were treated with or without 2 mM VPA for 24 h followed by irradiation. (A) 24 h after irradiation, the cell viabilities were determined by MTS assay. Immuno-blots showed the (B) protein expressions of p-cdc2, (C) cleavage of caspase-3 and PARP, and (D) expression of p-H2AX of MgSCs treated with VPA and irradiation. α-actinin, loading control. The quantification results are shown in the right panel. Bars, mean±SEM; *p < 0.05, **p < 0.01, and #p < 0.001 showed significant differences. Data are representative of 3 independent experiments.
Mentions: Despite the chemoresistance of MgSCs to vincristine [3], VPA induced more severe cell death in MgSCs than in MgACs (Figure 2). The MgSCs were treated with an IC50 dose of VPA (2 mM) and irradiation (5Gy) alone or in combination, and were subjected to MTS assay. The results revealed that MgSCs pre-treated with VPA had reduced cell viability with the use of irradiation compared to the untreated control (p < 0.01) (Figure 3A), indicating that VPA increased the radio-sensitivity of MgSCs. Moreover, p-cdc2 (Tyr15), which was elevated in the G2/M phase of the cell cycle [21], was significantly induced by the combined treatment, compared to the untreated control (p < 0.01) (Figure 3B). The cleavage of apoptotic proteins, caspase-3 and PARP was also induced by the combined treatment (Figure 3C). DNA damage-inducing p-H2AX [22] was also significantly induced by the combined treatment, compared to the untreated control (p < 0.001) (Figure 3D). These findings indicate that VPA enhanced the radiosensitivity of MgSCs and that combined treatment decreased MgSCs survival through mechanisms like cell cycle arrest, apoptosis and DNA fragmentation.

Bottom Line: Anchorage-independent growth (AIG) was reduced by VPA.AIG was further reduced by combined treatment with irradiation.Oct4 was further decreased by combined treatment with irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.

ABSTRACT
Although meningioma stem-like cells have been isolated and characterized, their therapeutic targeting remains a challenge. Meningioma sphere cells (MgSCs) with cancer stem cells properties show chemo- and radioresistance in comparison with meningioma adherent cells (MgACs). We tested the effect of valproic acid (VPA), a commonly used anti-epileptic drug, which passes the blood brain barrier, on cultured MgSCs. VPA reduced the viability of MgSCs and MgACs. In MgSCs, treatment with VPA increased radio-sensitivity, expression of p-cdc2, p-H2AX and cleaved caspase-3 and PARP. Anchorage-independent growth (AIG) was reduced by VPA. AIG was further reduced by combined treatment with irradiation. Expression of a stem cell marker, Oct4, was reduced by VPA. Oct4 was further decreased by combined treatment with irradiation. These results suggest that VPA may be a potential treatment for meningioma through targeting meningioma stem-like cells.

No MeSH data available.


Related in: MedlinePlus