Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy
Alok Ranjan1, Itishree Kaushik1,2, Sanjay K Srivastava1,2
1Department of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
Abstract:
Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC50 (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
Insights
Pimozide, a schizophrenia drug, effectively inhibits brain cancer cell growth and reduces tumor size in mice by triggering programmed cell death (apoptosis) through autophagy. This novel approach shows promise for treating aggressive brain tumors.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Brain tumors are aggressive cancers with poor prognoses, often resistant to current therapies.
- Existing treatments like surgery, chemotherapy, and radiotherapy have limited efficacy for many brain tumor patients.
Purpose of the Study:
- To investigate the anti-cancer potential of pimozide, a neuroleptic drug, against various human brain cancer cell lines.
- To elucidate the mechanism of action of pimozide in inhibiting brain tumor growth, focusing on apoptosis and autophagy pathways.
Main Methods:
- In vitro studies using U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines treated with pimozide.
- Western blotting to analyze protein expression (STAT3, Src, c-Myc, Mcl-1, Bcl-2, LC3B, Beclin-1, ATG5).
- In vivo studies involving intracranial implantation of U-87MG tumors in athymic nude mice treated with pimozide.
Main Results:
- Pimozide significantly inhibited brain cancer cell proliferation and induced apoptosis with IC50 values between 12-16 μM.
- Pimozide suppressed STAT3 and Src phosphorylation and decreased anti-apoptotic markers (c-Myc, Mcl-1, Bcl-2).
- Pimozide treatment strongly induced autophagy, confirmed by LC3B, Beclin-1, and ATG5 upregulation and autolysosome formation; blocking autophagy abolished pimozide's apoptotic effects.
- Oral administration of pimozide reduced U-87MG tumor growth by 45% in mice without observable toxicity.
Conclusions:
- Pimozide exhibits potent anti-brain tumor effects by inducing autophagy-mediated apoptosis.
- The findings suggest pimozide as a potential therapeutic agent for brain cancer treatment.
- Further research into pimozide's mechanism and efficacy is warranted for clinical application.
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