Abstract
Glioblastoma (GBM) is the most common brain tumor with poor survival rate. Our results show that penfluridol, an antipsychotic drug significantly reduced the survival of ten adult and pediatric glioblastoma cell lines with IC50 ranging 2–5 μM after 72 hours of treatment and induced apoptosis. Penfluridol treatment suppressed the phosphorylation of Akt at Ser473 and reduced the expression of GLI1, OCT4, Nanog and Sox2 in several glioblastoma cell lines in a concentration-dependent manner. Inhibiting Akt with LY294002 and siRNA, or inhibiting GLI1 using GANT61, cyclopamine, siRNA and CRISPR/Cas9 resulted in enhanced cell growth suppressive effects of penfluridol. On the other hand, overexpression of GLI1 significantly attenuated the effects of penfluridol. Our results further demonstrated that penfluridol treatment inhibited the growth of U87MG tumors by 65% and 72% in subcutaneous and intracranial in vivo glioblastoma tumor models respectively. Immunohistochemical and western blot analysis of tumors revealed reduced pAkt (Ser 473), GLI1, OCT4 and increase in caspase-3 cleavage and TUNEL staining, confirming in vitro findings. Taken together, our results indicate that overall glioblastoma tumor growth suppression by penfluridol was associated with Akt-mediated inhibition of GLI1.
Highlights
Glioblastoma (GBM) is one of the highly malignant and incurable brain tumors
Our current study demonstrated potential anticancer effects of penfluridol in vitro and in vivo against glioblastoma, which is known to be an incurable type of brain tumor
We observed that penfluridol treatment significantly reduced the viability of all the glioblastoma cells in a concentration and time-dependent manner with IC50 ranging between 3–5 μM after 48 h of treatment
Summary
Glioblastoma (GBM) is one of the highly malignant and incurable brain tumors. The median survival rate of glioblastoma patients is only 12%. Despite availability of several therapeutic alternatives, glioblastoma still claims thousands of lives each year. Three major obstacles which exist in current treatment strategies for glioblastoma are (a) recurrence of tumor within six months after surgical removal (b) development of resistance to chemotherapies, and (c) inability of the drugs to cross blood-brain-barrier (BBB) in order to reach the brain. Due to lack of effective treatment, 88% of glioblastoma patients succumb to death within three years after diagnosis. Glioblastoma is like a death sentence to the patients. It is critical to find new treatment options against this deadly disease
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