Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy
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 radio...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/9/2141 |
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| author | Alok Ranjan Itishree Kaushik Sanjay K. Srivastava |
| author_facet | Alok Ranjan Itishree Kaushik Sanjay K. Srivastava |
| author_sort | Alok Ranjan |
| collection | DOAJ |
| description | 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 IC<sub>50</sub> (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. |
| first_indexed | 2024-03-10T16:08:45Z |
| format | Article |
| id | doaj.art-73c49ef4d9ce44048138126d99b17661 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T16:08:45Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-73c49ef4d9ce44048138126d99b176612023-11-20T14:39:50ZengMDPI AGCells2073-44092020-09-0199214110.3390/cells9092141Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated AutophagyAlok Ranjan0Itishree Kaushik1Sanjay K. Srivastava2Department of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USADepartment of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USADepartment of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USABrain 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 IC<sub>50</sub> (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.https://www.mdpi.com/2073-4409/9/9/2141brain tumorautophagySTAT3drug repurposingmedulloblastomaglioblastoma |
| spellingShingle | Alok Ranjan Itishree Kaushik Sanjay K. Srivastava Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy Cells brain tumor autophagy STAT3 drug repurposing medulloblastoma glioblastoma |
| title | Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy |
| title_full | Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy |
| title_fullStr | Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy |
| title_full_unstemmed | Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy |
| title_short | Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy |
| title_sort | pimozide suppresses the growth of brain tumors by targeting stat3 mediated autophagy |
| topic | brain tumor autophagy STAT3 drug repurposing medulloblastoma glioblastoma |
| url | https://www.mdpi.com/2073-4409/9/9/2141 |
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