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Alok Ranjan - One of the best experts on this subject based on the ideXlab platform.
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Immune consequences of Penfluridol treatment associated with inhibition of glioblastoma tumor growth.
Oncotarget, 2017Co-Authors: Alok Ranjan, Stephen E. Wright, Sanjay K. SrivastavaAbstract:// Alok Ranjan 1 , Stephen Wright 1, 2 and Sanjay K. Srivastava 1, 3 1 Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 2 Departments of Internal Medicine and Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 3 Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79106, USA Correspondence to: Sanjay K. Srivastava, email: sanjay.srivastava@ttuhsc.edu Keywords: MDSC, glioblastoma, anti-psychotic drug, Treg, macrophages Abbreviations: PBMC: peripheral blood mononuclear cells; MDSC: myeloid derived suppressor cells; GBM: Glioblastoma multiforme; Treg: regulatory T cells Received: October 20, 2016 Accepted: March 13, 2017 Published: April 26, 2017 ABSTRACT Glioblastoma is the most common and lethal brain tumor associated with only 12% median survival rate of patients. Despite the development of advanced surgical, radiation or use of combinations of anti-cancer drugs, treatment for glioblastoma patients is still a challenge. The major contributing factor in glioblastoma progression and resistive nature is its ability to evade the immune surveillance. Hence, modulating the immune system in glioblastoma tumors could be an important strategy for anticancer therapeutics. Penfluridol, an antipsychotic drug has been shown to have anti-cancer properties in our recently published studies. The present study evaluates the immune response of Penfluridol in glioblastoma tumors. Our results demonstrated that Penfluridol treatment significantly suppressed glioblastoma tumor growth. Our current results demonstrated about 72% suppression of myeloid derived suppressor cells (MDSCs) with Penfluridol treatment in mouse bearing U87MG glioblastoma tumors. MDSCs are known to increase regulatory T cells (Treg), which are immunosuppressive in nature and suppresses M1 macrophages that are tumor suppressive in nature. Our results also showed suppression of regulatory T cells as well as elevation of M1 macrophages with Penfluridol treatment by 58% and 57% respectively. Decrease in CCL4 as well as IFNγ with Penfluridol treatment was also observed indicating decrease in overall tumor inflammation. This is the first report demonstrating immune modulations by Penfluridol treatment associated with glioblastoma tumor growth suppression prompting further investigation to establish Penfluridol as a treatment option for glioblastoma patients.
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Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1.
Oncotarget, 2017Co-Authors: Alok Ranjan, Sanjay K. SrivastavaAbstract:// Alok Ranjan 1 , Sanjay K. Srivastava 1, 2 1 Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 2 Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA Correspondence to: Sanjay K. Srivastava, email: sanjay.srivastava@ttuhsc.edu Keywords: antipsychotic drug, glioblastoma, neurosphere, in vivo, intracranial Received: December 16, 2016 Accepted: March 03, 2017 Published: March 23, 2017 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 IC 50 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.
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Abstract 2915: Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling
Molecular and Cellular Biology Genetics, 2016Co-Authors: Alok Ranjan, Sanjay K. SrivastavaAbstract:Glioblastoma (GBM) is the most common brain tumor with poor survival rate. The main obstacle in the treatment of glioblastoma patients is the presence of blood brain barrier, which restricts the movement of the drugs to reach the brain. Penfluridol (PF) is known to cross blood brain barrier and is a clinically approved drug for schizophrenia patients. It is demonstrated and established by us that Penfluridol suppresses the growth of metastasized breast cancer cells in brain giving us the rationale to evaluate it against glioblastoma (Alok Ranjan, Parul Gupta and Sanjay Srivastava, Cancer Research 2015). Penfluridol significantly reduced the viability of U87-MG, T98G and U251 MG glioblastoma cells with an IC50 of 6μM, 5.5μM and 9μM respectively after 24 h of treatment and induced apoptosis as exhibited by FITC/Annexin assay and cleavage of caspase 3 as well as PARP. It has been shown that GLI1, a transcription factor belonging to sonic hedgehog signaling is overexpressed in GBM and responsible for tumor progression. Our results demonstrated that Penfluridol treatment reduced the expression of GLI1 in U87MG, T98G and U251 MG cells in concentration-dependent manner. In addition, overexpression of MGMT, a DNA repair enzyme has been linked to temozolomide (TMZ) resistance in GBM therapy. Combination of PF and TMZ induced more apoptosis and reduced the expression of GLI1 and MGMT as compared to PF or TMZ treatment alone. Our results further demonstrated that oral administration of PF inhibited the growth of GBM tumors by 66% and 72% in subcutaneous and intracranial GBM tumor model respectively. Immunohistochemical analysis of tumor tissue and western blot analysis of tumor lysate indicated down regulation of GLI1, MGMT and increase in cleavage of caspase 3, confirming in vitro finding. Apoptosis induction effect of PF treatment in tumor tissues was further confirmed by Tunel staining. Taken together, these results indicate that overall GBM tumor growth suppression by Penfluridol was associated with inhibition of Gli1 and induction of apoptosis Citation Format: Alok Ranjan, Sanjay K. Srivastava. Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2915.
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Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis
Scientific reports, 2016Co-Authors: Alok Ranjan, Sanjay K. SrivastavaAbstract:Pancreatic tumors exhibit enhanced autophagy as compared to any other cancer, making it resistant to chemotherapy. We evaluated the effect of Penfluridol against pancreatic cancer. Penfluridol treatment induced apoptosis and inhibited the growth of Panc-1, BxPC-3 and AsPC-1, pancreatic cancer cells with IC50 ranging between 6-7 μM after 24 h of treatment. Significant autophagy was induced by Penfluridol treatment in pancreatic cancer cells. Punctate LC3B and autophagosomes staining confirmed autophagy. Inhibiting autophagy by chloroquine, bafilomycin, 3-methyladenine or LC3BsiRNA, significantly blocked Penfluridol-induced apoptosis, suggesting that autophagy lead to apoptosis in our model. Penfluridol treatment suppressed the growth of BxPC-3 tumor xenografts by 48% as compared to 17% when treated in combination with chloroquine. Similarly, Penfluridol suppressed the growth of AsPC-1 tumors by 40% versus 16% when given in combination with chloroquine. TUNEL staining and caspase-3 cleavage revealed less apoptosis in the tumors from mice treated with Penfluridol and chloroquine as compared to Penfluridol alone. Penfluridol treatment also suppressed the growth of orthotopically implanted Panc-1 tumors by 80% by inducing autophagy-mediated apoptosis in the tumors. These studies established that Penfluridol inhibits pancreatic tumor growth by autophagy-mediated apoptosis. Since Penfluridol is already in clinic, positive findings from our study will accelerate its clinical development.
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Abstract A68: Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling
Other Topics, 2016Co-Authors: Alok Ranjan, Parul Gupta, Sanjay K. SrivastavaAbstract:Breast cancer is the second leading cause of cancer related deaths in US. Breast tumor metastasis to brain is major cause of deaths. Brain metastasis of triple negative breast cancer cells (TNBC) is highly resistant to current therapies and is a cause of reduced survival rates in patients. In current study, we evaluated Penfluridol, a first generation, highly potent antipsychotic drug against three different highly aggressive TNBC cell line. The IC50 of Penfluridol was around 6 µM in 4T1, MDA-MB-231 and HCC-1806, breast cancer cells respectively. Our result showed that the expression of integrinβ4, integrinα6, Fak, Paxillin, Rac1/2/3 and ROCK1 was significantly reduced after 24 hours of treatment with Penfluridol. We also observed that Penfluridol treatment induced significant apoptosis in 4T1, MDA-MB-231 and HCC-1806, TNBC cells as exbited by cleavage of caspase 3. Interestingly, integrin signaling is known to play significant role in breast cancer metastasis and integrinα6β4 are overexpressed in breast tumors. Integrinα6 and β4 were silenced in breast cancer cells using shRNA and siRNA respectively. Silencing integrinα6β4 resulted in apoptosis which was further increased by Penfluridol treatment. On the other hand, activation of integrins by TGFβ treatment and Laminin reduced induction of apoptosis by Penfluridol confirming the role of integrins. We further evaluated the efficacy of Penfluridol in three independent invivo experiments. In the first experiment, we implanted 4T1, breast cancer cells in the mammary fats of female mice and started treatment once tumor size was around 50 mm3 with 10 mg/kg Penfluridol by oral gavage everyday till day 27. Penfluridol treatment suppressed breast tumor growth by 50% as compared to control. In the second experiment, 4T1 luciferase transfected breast cancer cells were injected intracranially into the brain. The growth of 4T1-luc cells was monitored non-invasively using IVIS caliper and the mice started getting treatment with 10 mg/kg Penfluridol by oral gavage the next day of cells injection. Our result demonstrated that the tumor growth in the brain of Penfluridol treated mice was reduced by 72% as compared to control. Further anti metastatic effect of Penfluridol was determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Once breast cancer cells lodged in the brain, mice were treated with 10 mg/kg Penfluridol for 12 days. Our results showed that Penfluridol treatment suppressed the metastasis of breast cancer cells to brain by 90%. The tumors obtained from PF treated mice from all the three different in vivo experiments exhibited reduced integrinβ4 and increased apoptosis. In addition, chronic administration of PF failed to exhibit any serious toxicity or behavioral side effects in mice. Taken together, our result indicate that PF is effective in reducing the growth of primary TNBC tumor as well as metastatic growth in brain by inhibiting integrin signaling. Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A68.
Sanjay K. Srivastava - One of the best experts on this subject based on the ideXlab platform.
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Immune consequences of Penfluridol treatment associated with inhibition of glioblastoma tumor growth.
Oncotarget, 2017Co-Authors: Alok Ranjan, Stephen E. Wright, Sanjay K. SrivastavaAbstract:// Alok Ranjan 1 , Stephen Wright 1, 2 and Sanjay K. Srivastava 1, 3 1 Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 2 Departments of Internal Medicine and Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 3 Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79106, USA Correspondence to: Sanjay K. Srivastava, email: sanjay.srivastava@ttuhsc.edu Keywords: MDSC, glioblastoma, anti-psychotic drug, Treg, macrophages Abbreviations: PBMC: peripheral blood mononuclear cells; MDSC: myeloid derived suppressor cells; GBM: Glioblastoma multiforme; Treg: regulatory T cells Received: October 20, 2016 Accepted: March 13, 2017 Published: April 26, 2017 ABSTRACT Glioblastoma is the most common and lethal brain tumor associated with only 12% median survival rate of patients. Despite the development of advanced surgical, radiation or use of combinations of anti-cancer drugs, treatment for glioblastoma patients is still a challenge. The major contributing factor in glioblastoma progression and resistive nature is its ability to evade the immune surveillance. Hence, modulating the immune system in glioblastoma tumors could be an important strategy for anticancer therapeutics. Penfluridol, an antipsychotic drug has been shown to have anti-cancer properties in our recently published studies. The present study evaluates the immune response of Penfluridol in glioblastoma tumors. Our results demonstrated that Penfluridol treatment significantly suppressed glioblastoma tumor growth. Our current results demonstrated about 72% suppression of myeloid derived suppressor cells (MDSCs) with Penfluridol treatment in mouse bearing U87MG glioblastoma tumors. MDSCs are known to increase regulatory T cells (Treg), which are immunosuppressive in nature and suppresses M1 macrophages that are tumor suppressive in nature. Our results also showed suppression of regulatory T cells as well as elevation of M1 macrophages with Penfluridol treatment by 58% and 57% respectively. Decrease in CCL4 as well as IFNγ with Penfluridol treatment was also observed indicating decrease in overall tumor inflammation. This is the first report demonstrating immune modulations by Penfluridol treatment associated with glioblastoma tumor growth suppression prompting further investigation to establish Penfluridol as a treatment option for glioblastoma patients.
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Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1.
Oncotarget, 2017Co-Authors: Alok Ranjan, Sanjay K. SrivastavaAbstract:// Alok Ranjan 1 , Sanjay K. Srivastava 1, 2 1 Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA 2 Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA Correspondence to: Sanjay K. Srivastava, email: sanjay.srivastava@ttuhsc.edu Keywords: antipsychotic drug, glioblastoma, neurosphere, in vivo, intracranial Received: December 16, 2016 Accepted: March 03, 2017 Published: March 23, 2017 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 IC 50 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.
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Abstract 2915: Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling
Molecular and Cellular Biology Genetics, 2016Co-Authors: Alok Ranjan, Sanjay K. SrivastavaAbstract:Glioblastoma (GBM) is the most common brain tumor with poor survival rate. The main obstacle in the treatment of glioblastoma patients is the presence of blood brain barrier, which restricts the movement of the drugs to reach the brain. Penfluridol (PF) is known to cross blood brain barrier and is a clinically approved drug for schizophrenia patients. It is demonstrated and established by us that Penfluridol suppresses the growth of metastasized breast cancer cells in brain giving us the rationale to evaluate it against glioblastoma (Alok Ranjan, Parul Gupta and Sanjay Srivastava, Cancer Research 2015). Penfluridol significantly reduced the viability of U87-MG, T98G and U251 MG glioblastoma cells with an IC50 of 6μM, 5.5μM and 9μM respectively after 24 h of treatment and induced apoptosis as exhibited by FITC/Annexin assay and cleavage of caspase 3 as well as PARP. It has been shown that GLI1, a transcription factor belonging to sonic hedgehog signaling is overexpressed in GBM and responsible for tumor progression. Our results demonstrated that Penfluridol treatment reduced the expression of GLI1 in U87MG, T98G and U251 MG cells in concentration-dependent manner. In addition, overexpression of MGMT, a DNA repair enzyme has been linked to temozolomide (TMZ) resistance in GBM therapy. Combination of PF and TMZ induced more apoptosis and reduced the expression of GLI1 and MGMT as compared to PF or TMZ treatment alone. Our results further demonstrated that oral administration of PF inhibited the growth of GBM tumors by 66% and 72% in subcutaneous and intracranial GBM tumor model respectively. Immunohistochemical analysis of tumor tissue and western blot analysis of tumor lysate indicated down regulation of GLI1, MGMT and increase in cleavage of caspase 3, confirming in vitro finding. Apoptosis induction effect of PF treatment in tumor tissues was further confirmed by Tunel staining. Taken together, these results indicate that overall GBM tumor growth suppression by Penfluridol was associated with inhibition of Gli1 and induction of apoptosis Citation Format: Alok Ranjan, Sanjay K. Srivastava. Penfluridol suppresses glioblastoma tumor growth by inhibiting sonic hedgehog signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2915.
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Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis
Scientific reports, 2016Co-Authors: Alok Ranjan, Sanjay K. SrivastavaAbstract:Pancreatic tumors exhibit enhanced autophagy as compared to any other cancer, making it resistant to chemotherapy. We evaluated the effect of Penfluridol against pancreatic cancer. Penfluridol treatment induced apoptosis and inhibited the growth of Panc-1, BxPC-3 and AsPC-1, pancreatic cancer cells with IC50 ranging between 6-7 μM after 24 h of treatment. Significant autophagy was induced by Penfluridol treatment in pancreatic cancer cells. Punctate LC3B and autophagosomes staining confirmed autophagy. Inhibiting autophagy by chloroquine, bafilomycin, 3-methyladenine or LC3BsiRNA, significantly blocked Penfluridol-induced apoptosis, suggesting that autophagy lead to apoptosis in our model. Penfluridol treatment suppressed the growth of BxPC-3 tumor xenografts by 48% as compared to 17% when treated in combination with chloroquine. Similarly, Penfluridol suppressed the growth of AsPC-1 tumors by 40% versus 16% when given in combination with chloroquine. TUNEL staining and caspase-3 cleavage revealed less apoptosis in the tumors from mice treated with Penfluridol and chloroquine as compared to Penfluridol alone. Penfluridol treatment also suppressed the growth of orthotopically implanted Panc-1 tumors by 80% by inducing autophagy-mediated apoptosis in the tumors. These studies established that Penfluridol inhibits pancreatic tumor growth by autophagy-mediated apoptosis. Since Penfluridol is already in clinic, positive findings from our study will accelerate its clinical development.
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Abstract A68: Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling
Other Topics, 2016Co-Authors: Alok Ranjan, Parul Gupta, Sanjay K. SrivastavaAbstract:Breast cancer is the second leading cause of cancer related deaths in US. Breast tumor metastasis to brain is major cause of deaths. Brain metastasis of triple negative breast cancer cells (TNBC) is highly resistant to current therapies and is a cause of reduced survival rates in patients. In current study, we evaluated Penfluridol, a first generation, highly potent antipsychotic drug against three different highly aggressive TNBC cell line. The IC50 of Penfluridol was around 6 µM in 4T1, MDA-MB-231 and HCC-1806, breast cancer cells respectively. Our result showed that the expression of integrinβ4, integrinα6, Fak, Paxillin, Rac1/2/3 and ROCK1 was significantly reduced after 24 hours of treatment with Penfluridol. We also observed that Penfluridol treatment induced significant apoptosis in 4T1, MDA-MB-231 and HCC-1806, TNBC cells as exbited by cleavage of caspase 3. Interestingly, integrin signaling is known to play significant role in breast cancer metastasis and integrinα6β4 are overexpressed in breast tumors. Integrinα6 and β4 were silenced in breast cancer cells using shRNA and siRNA respectively. Silencing integrinα6β4 resulted in apoptosis which was further increased by Penfluridol treatment. On the other hand, activation of integrins by TGFβ treatment and Laminin reduced induction of apoptosis by Penfluridol confirming the role of integrins. We further evaluated the efficacy of Penfluridol in three independent invivo experiments. In the first experiment, we implanted 4T1, breast cancer cells in the mammary fats of female mice and started treatment once tumor size was around 50 mm3 with 10 mg/kg Penfluridol by oral gavage everyday till day 27. Penfluridol treatment suppressed breast tumor growth by 50% as compared to control. In the second experiment, 4T1 luciferase transfected breast cancer cells were injected intracranially into the brain. The growth of 4T1-luc cells was monitored non-invasively using IVIS caliper and the mice started getting treatment with 10 mg/kg Penfluridol by oral gavage the next day of cells injection. Our result demonstrated that the tumor growth in the brain of Penfluridol treated mice was reduced by 72% as compared to control. Further anti metastatic effect of Penfluridol was determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Once breast cancer cells lodged in the brain, mice were treated with 10 mg/kg Penfluridol for 12 days. Our results showed that Penfluridol treatment suppressed the metastasis of breast cancer cells to brain by 90%. The tumors obtained from PF treated mice from all the three different in vivo experiments exhibited reduced integrinβ4 and increased apoptosis. In addition, chronic administration of PF failed to exhibit any serious toxicity or behavioral side effects in mice. Taken together, our result indicate that PF is effective in reducing the growth of primary TNBC tumor as well as metastatic growth in brain by inhibiting integrin signaling. Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A68.
Sanjay Srivastava - One of the best experts on this subject based on the ideXlab platform.
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Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis.
International journal of molecular sciences, 2020Co-Authors: Suyash Srivastava, Sanjay Srivastava, Fatema Tuz Zahra, Nehal Gupta, Paul E. Tullar, Constantinos M. MikelisAbstract:: Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood-brain barrier. Recent studies have revealed that Penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of Penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of Penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, Penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by Penfluridol treatment. When cancer cells were treated with the same low concentration of Penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low Penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.
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abstract lb 195 Penfluridol an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting her2 akt mmp signaling axis in a novel in vivo metastasis model
Cancer Research, 2014Co-Authors: Alok Ranjan, Parul Gupta, Sanjay SrivastavaAbstract:Breast tumor metastasis is primary cause of cancer-related deaths. Metastasis is a complex process involving cell migration and invasion of tumor cells to distant organs from primary sites. Brain metastasis is a frequent cause of reduced survival of breast cancer patients. In the current study, we evaluated the anti-metastatic effects of Penfluridol, a first generation highly potent antipsychotic drug in a novel murine model of breast tumor metastasis to brain. 4T1 breast tumor cells with stable luciferase expression were injected into the left ventricle of mouse heart. The migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent live animal imaging system. To evaluate the anti-metastatic effects, 10mg/kg Penfluridol was administered orally to mice every day for 12 days after intra-cardiac injection of tumor cells. The growth rate of metastasized tumors cells in control and treated mice was determined by measuring the luminescence in the brain area in each mouse at different time points. Our results demonstrate that the growth of metastatic brain tumors was reduced by 82% in the mice treated with Penfluridol. In addition, treatment of 4T1, MCF-7 or MDA-MB-231 cells with 10µM Penfluridol for 24 hours resulted in the significantly reduced migration and 30-40% reduced invasion of cells, as evaluated by wound healing and Boyden9s transwell invasion assay respectively. Penfluridol treatment also reduced the expression of HER2, AKT and MMP-2, 9 in these cells. Interestingly, overexpression of HER2 led to the phosphorylation of Akt, which in turn is known to regulate MMPs. Taken together, our results indicate that the anti-metastatic effects of Penfluridol were associated with down regulation of HER2, AKT and MMPs. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of Penfluridol in vivo in a novel breast tumor metastasis model. Most importantly, Penfluridol is already in clinical use with an established safety record; therefore any positive findings from our studies can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced metastatic breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH] Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-195. doi:10.1158/1538-7445.AM2014-LB-195
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Abstract 1251: Repurposing antipsychotic drug Penfluridol for cancer treatment
Prevention Research, 2014Co-Authors: Alok Ranjan, Sanjay SrivastavaAbstract:Repurposing of old drugs as new anti-cancer drugs is important as it can save time and cost of drug development. Penfluridol is a first generation, highly potent antipsychotic drug. In this study, we determined the anticancer effects of Penfluridol in pancreatic cancer cells. Penfluridol treatment inhibited the growth of Panc-1, BxPC-3 and AsPC-1 pancreatic cancer cells in a concentration-dependent manner. Panc-1 , BxPC-3 and AsPC-1 cells treated with Penfluridol exhibited apoptosis as evaluated by Annexin/FITC assay and cleavage of caspase-3 and PARP. Our results showed that Penfluridol treatment induced ER stress in pancreatic cancer cells through the up regulation of ER stress markers like Bip/Grp78, CHOP and IRE. Penfluridol treatment also induced autophagy in pancreatic cancer cells as observed by acridine orange assay. Western blot analysis of Panc-1, BxPC-3 and AsPC-1 cells treated with Penfluridol exhibited up regulation of autophagy markers like LC3B, and p62. Microscopic analysis revealed punctate LC3B after Penfluridol treatment in pancreatic cancer cells confirming autophagy. Further mechanistic studies are in progress to establish the role of ER stress and autophagy in pancreatic cancer cells and correlate it with cell growth suppression. [Supported in part by R01 grant CA129038 awarded by NIH.] Citation Format: Alok Ranjan, Sanjay K. Srivastava. Repurposing antipsychotic drug Penfluridol for cancer treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1251. doi:10.1158/1538-7445.AM2014-1251
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Abstract LB-195: Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model
Tumor Biology, 2014Co-Authors: Alok Ranjan, Parul Gupta, Sanjay SrivastavaAbstract:Breast tumor metastasis is primary cause of cancer-related deaths. Metastasis is a complex process involving cell migration and invasion of tumor cells to distant organs from primary sites. Brain metastasis is a frequent cause of reduced survival of breast cancer patients. In the current study, we evaluated the anti-metastatic effects of Penfluridol, a first generation highly potent antipsychotic drug in a novel murine model of breast tumor metastasis to brain. 4T1 breast tumor cells with stable luciferase expression were injected into the left ventricle of mouse heart. The migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent live animal imaging system. To evaluate the anti-metastatic effects, 10mg/kg Penfluridol was administered orally to mice every day for 12 days after intra-cardiac injection of tumor cells. The growth rate of metastasized tumors cells in control and treated mice was determined by measuring the luminescence in the brain area in each mouse at different time points. Our results demonstrate that the growth of metastatic brain tumors was reduced by 82% in the mice treated with Penfluridol. In addition, treatment of 4T1, MCF-7 or MDA-MB-231 cells with 10µM Penfluridol for 24 hours resulted in the significantly reduced migration and 30-40% reduced invasion of cells, as evaluated by wound healing and Boyden9s transwell invasion assay respectively. Penfluridol treatment also reduced the expression of HER2, AKT and MMP-2, 9 in these cells. Interestingly, overexpression of HER2 led to the phosphorylation of Akt, which in turn is known to regulate MMPs. Taken together, our results indicate that the anti-metastatic effects of Penfluridol were associated with down regulation of HER2, AKT and MMPs. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of Penfluridol in vivo in a novel breast tumor metastasis model. Most importantly, Penfluridol is already in clinical use with an established safety record; therefore any positive findings from our studies can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced metastatic breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH] Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-195. doi:10.1158/1538-7445.AM2014-LB-195
Parul Gupta - One of the best experts on this subject based on the ideXlab platform.
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Abstract A68: Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling
Other Topics, 2016Co-Authors: Alok Ranjan, Parul Gupta, Sanjay K. SrivastavaAbstract:Breast cancer is the second leading cause of cancer related deaths in US. Breast tumor metastasis to brain is major cause of deaths. Brain metastasis of triple negative breast cancer cells (TNBC) is highly resistant to current therapies and is a cause of reduced survival rates in patients. In current study, we evaluated Penfluridol, a first generation, highly potent antipsychotic drug against three different highly aggressive TNBC cell line. The IC50 of Penfluridol was around 6 µM in 4T1, MDA-MB-231 and HCC-1806, breast cancer cells respectively. Our result showed that the expression of integrinβ4, integrinα6, Fak, Paxillin, Rac1/2/3 and ROCK1 was significantly reduced after 24 hours of treatment with Penfluridol. We also observed that Penfluridol treatment induced significant apoptosis in 4T1, MDA-MB-231 and HCC-1806, TNBC cells as exbited by cleavage of caspase 3. Interestingly, integrin signaling is known to play significant role in breast cancer metastasis and integrinα6β4 are overexpressed in breast tumors. Integrinα6 and β4 were silenced in breast cancer cells using shRNA and siRNA respectively. Silencing integrinα6β4 resulted in apoptosis which was further increased by Penfluridol treatment. On the other hand, activation of integrins by TGFβ treatment and Laminin reduced induction of apoptosis by Penfluridol confirming the role of integrins. We further evaluated the efficacy of Penfluridol in three independent invivo experiments. In the first experiment, we implanted 4T1, breast cancer cells in the mammary fats of female mice and started treatment once tumor size was around 50 mm3 with 10 mg/kg Penfluridol by oral gavage everyday till day 27. Penfluridol treatment suppressed breast tumor growth by 50% as compared to control. In the second experiment, 4T1 luciferase transfected breast cancer cells were injected intracranially into the brain. The growth of 4T1-luc cells was monitored non-invasively using IVIS caliper and the mice started getting treatment with 10 mg/kg Penfluridol by oral gavage the next day of cells injection. Our result demonstrated that the tumor growth in the brain of Penfluridol treated mice was reduced by 72% as compared to control. Further anti metastatic effect of Penfluridol was determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Once breast cancer cells lodged in the brain, mice were treated with 10 mg/kg Penfluridol for 12 days. Our results showed that Penfluridol treatment suppressed the metastasis of breast cancer cells to brain by 90%. The tumors obtained from PF treated mice from all the three different in vivo experiments exhibited reduced integrinβ4 and increased apoptosis. In addition, chronic administration of PF failed to exhibit any serious toxicity or behavioral side effects in mice. Taken together, our result indicate that PF is effective in reducing the growth of primary TNBC tumor as well as metastatic growth in brain by inhibiting integrin signaling. Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol suppresses triple-negative breast cancer metastasis to brain by inhibiting integrin signaling. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A68.
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Penfluridol an antipsychotic agent suppresses metastatic tumor growth in triple negative breast cancer by inhibiting integrin signaling axis
Cancer Research, 2016Co-Authors: Alok Ranjan, Parul Gupta, Sanjay K. SrivastavaAbstract:Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. In the current study, we investigated the antimetastatic potential of Penfluridol, an antipsychotic drug frequently prescribed for schizophrenia with anticancer activity. We show that Penfluridol induced apoptosis and reduced the survival of several metastatic triple-negative breast cancer (TNBC) cell lines. In addition, Penfluridol treatment significantly reduced the expression of integrin α6, integrin β4, Fak, paxillin, Rac1/2/3, and ROCK1 in vitro. We further evaluated the efficacy of Penfluridol in three different in vivo tumor models. We demonstrate that Penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, Penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin β4 and increased apoptosis. Moreover, chronic administration of Penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that Penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing Penfluridol for the treatment of metastatic TNBC.
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Abstract 5504: Penfluridol suppresses triple negative breast cancer metastasis to brain by inhibiting α6β4 integrins
Experimental and Molecular Therapeutics, 2015Co-Authors: Alok Ranjan, Parul Gupta, Sanjay K. SrivastavaAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Breast cancer is the second leading cause of cancer related deaths in the United States. Breast tumor metastasis to brain is primary cause of deaths. Brain metastasis of triple negative breast cancer cells (TNBC) is highly resistant to current therapies and is a cause of reduced survival rates in patients. In the current study, we evaluated the anti-cancer effects of Penfluridol, a first generation antipsychotic drug against three different highly aggressive TNBC cell line. The IC50 of Penfluridol was around 6 μM in 4T1, MDA-MB-231 and HCC-1806, breast cancer cells respectively. Our result showed that the expression of integrinβ4, integrinα6, Fak, Paxillin, Rac1/2/3 and ROCK1 was significantly reduced after treatment with Penfluridol for 24 hours. Penfluridol treatment induced significant apoptosis in 4T1, MDA-MB-231 and HCC-1806 cells as exhibited by cleavage of caspase 3. Interestingly, integrin signaling is known to play significant role in breast cancer metastasis, and integrinα6β4 are overexpressed in breast tumors. Integrinα6 and β4 were silenced in breast cancer cells using shRNA and siRNA respectively. Silencing of integrinα6β4 resulted in apoptosis which was further increased by Penfluridol treatment. On the other hand, activation of integrins by TGFβ treatment reduced the induction of apoptosis by Penfluridol, confirming the role of integrins. Efficacy of Penfluridol was evaluated in three in vivo experiments. In the first experiment, 4T1, breast cancer cells were implanted in the mammary fat pads of female mice and the mice were treated with 10 mg/kg Penfluridol by oral gavage everyday till day 27, once the tumor size reached 50 mm3. Penfluridol treatment suppressed breast tumor growth by 50% as compared to control. In the second experiment, 4T1 luciferase transfected breast cancer cells were injected intracranially into the brain. The growth of 4T1-luc cells was monitored non-invasively using IVIS caliper and the mice started getting treatment with 10 mg/kg Penfluridol by oral gavage the very next day of tumor cell injection. Our result demonstrated that the tumor growth in the brain of Penfluridol treated mice was reduced by 85% as compared to control. Furthermore, anti-metastatic effect of Penfluridol was determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Once breast cancer cells lodged in the brain, mice were treated with 10 mg/kg Penfluridol for 12 days. Our results showed that Penfluridol treatment suppressed the growth of metastatic breast cancer cells in brain by 90%. The metastatic tumors from Penfluridol treated mice exhibited reduced expression of integrins. Taken together, our result indicate that Penfluridol is effective in reducing the growth of primary TNBC tumor as well as metastatic growth in brain by inhibiting integrin signaling. [Supported in part by R01 grant CA129038, awarded by National Cancer Institute, NIH]. Citation Format: Alok Ranjan, Parul Gupta, Sanjay Srivastava. Penfluridol suppresses triple negative breast cancer metastasis to brain by inhibiting α6β4 integrins. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5504. doi:10.1158/1538-7445.AM2015-5504
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abstract lb 195 Penfluridol an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting her2 akt mmp signaling axis in a novel in vivo metastasis model
Cancer Research, 2014Co-Authors: Alok Ranjan, Parul Gupta, Sanjay SrivastavaAbstract:Breast tumor metastasis is primary cause of cancer-related deaths. Metastasis is a complex process involving cell migration and invasion of tumor cells to distant organs from primary sites. Brain metastasis is a frequent cause of reduced survival of breast cancer patients. In the current study, we evaluated the anti-metastatic effects of Penfluridol, a first generation highly potent antipsychotic drug in a novel murine model of breast tumor metastasis to brain. 4T1 breast tumor cells with stable luciferase expression were injected into the left ventricle of mouse heart. The migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent live animal imaging system. To evaluate the anti-metastatic effects, 10mg/kg Penfluridol was administered orally to mice every day for 12 days after intra-cardiac injection of tumor cells. The growth rate of metastasized tumors cells in control and treated mice was determined by measuring the luminescence in the brain area in each mouse at different time points. Our results demonstrate that the growth of metastatic brain tumors was reduced by 82% in the mice treated with Penfluridol. In addition, treatment of 4T1, MCF-7 or MDA-MB-231 cells with 10µM Penfluridol for 24 hours resulted in the significantly reduced migration and 30-40% reduced invasion of cells, as evaluated by wound healing and Boyden9s transwell invasion assay respectively. Penfluridol treatment also reduced the expression of HER2, AKT and MMP-2, 9 in these cells. Interestingly, overexpression of HER2 led to the phosphorylation of Akt, which in turn is known to regulate MMPs. Taken together, our results indicate that the anti-metastatic effects of Penfluridol were associated with down regulation of HER2, AKT and MMPs. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of Penfluridol in vivo in a novel breast tumor metastasis model. Most importantly, Penfluridol is already in clinical use with an established safety record; therefore any positive findings from our studies can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced metastatic breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH] Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-195. doi:10.1158/1538-7445.AM2014-LB-195
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Abstract LB-195: Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model
Tumor Biology, 2014Co-Authors: Alok Ranjan, Parul Gupta, Sanjay SrivastavaAbstract:Breast tumor metastasis is primary cause of cancer-related deaths. Metastasis is a complex process involving cell migration and invasion of tumor cells to distant organs from primary sites. Brain metastasis is a frequent cause of reduced survival of breast cancer patients. In the current study, we evaluated the anti-metastatic effects of Penfluridol, a first generation highly potent antipsychotic drug in a novel murine model of breast tumor metastasis to brain. 4T1 breast tumor cells with stable luciferase expression were injected into the left ventricle of mouse heart. The migration of cells to brain was monitored using a non-invasive IVIS bio-luminescent live animal imaging system. To evaluate the anti-metastatic effects, 10mg/kg Penfluridol was administered orally to mice every day for 12 days after intra-cardiac injection of tumor cells. The growth rate of metastasized tumors cells in control and treated mice was determined by measuring the luminescence in the brain area in each mouse at different time points. Our results demonstrate that the growth of metastatic brain tumors was reduced by 82% in the mice treated with Penfluridol. In addition, treatment of 4T1, MCF-7 or MDA-MB-231 cells with 10µM Penfluridol for 24 hours resulted in the significantly reduced migration and 30-40% reduced invasion of cells, as evaluated by wound healing and Boyden9s transwell invasion assay respectively. Penfluridol treatment also reduced the expression of HER2, AKT and MMP-2, 9 in these cells. Interestingly, overexpression of HER2 led to the phosphorylation of Akt, which in turn is known to regulate MMPs. Taken together, our results indicate that the anti-metastatic effects of Penfluridol were associated with down regulation of HER2, AKT and MMPs. To the best of our knowledge, our study for the first time demonstrates the anti-metastatic effects of Penfluridol in vivo in a novel breast tumor metastasis model. Most importantly, Penfluridol is already in clinical use with an established safety record; therefore any positive findings from our studies can be rapidly translated to the clinics for undertaking a clinical trial to treat advanced metastatic breast cancer patients. [Supported in part by R01 grant CA 129038 awarded by National Cancer Institute, NIH] Citation Format: Alok Ranjan, Parul Gupta, Sanjay K. Srivastava. Penfluridol, an antipsychotic drug suppresses breast cancer metastasis to brain by inhibiting HER2/Akt/MMP signaling axis in a novel in vivo metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-195. doi:10.1158/1538-7445.AM2014-LB-195
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The Cochrane Library - Chlorpromazine versus Penfluridol for schizophrenia
The Cochrane database of systematic reviews, 2017Co-Authors: Naemeh Nikvarz, Mostafa Vahedian, Navid KhaliliAbstract:Background The efficacy of chlorpromazine, a benchmark antipsychotic, has not been fully assessed in direct comparison with different individual antipsychotics. Penfluridol is another old antipsychotic with a long half-life so one oral dose may last up to one week. This could confer advantage. Objectives To assess the clinical effects of chlorpromazine compared with Penfluridol for adults with schizophrenia. Search methods On 31 March 2017, we searched the Cochrane Schizophrenia Group’s Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. Selection criteria We included all randomised clinical trials focusing on chlorpromazine versus Penfluridol for adults with schizophrenia or related disorders. Outcomes of interest were death, service utilisation, global state, mental state, adverse effects and leaving the study early. We included trials meeting our selection criteria and reporting useable data. Data collection and analysis We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we planned to estimate the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. Main results The review includes three studies with a total of 130 participants. Short-term results for hospital admissions showed no clear difference between chlorpromazine and Penfluridol (1 RCT, n = 29, RR 0.19, 95% CI 0.01 to 3.60, low-quality evidence). No clear difference in the incidence of akathisia was found at medium term (2 RCTs, n = 85, RR 0.19, 95% CI 0.04 to 1.06, low-quality evidence), and similar numbers of participants - nearly half - from each treatment group left the study early (3 RCTs, n = 130, RR 1.21, 95% CI 0.83 to 1.77, low-quality evidence). The risk of needing additional antiparkinsonian medication was less in the chlorpromazine group (2 RCTs, n = 74, RR 0.70, 95% CI 0.51 to 0.95). No useable data reported clinically important change in global or mental state. No data were reported for relapse. No deaths were reported by the trials. Authors' conclusions Only three small studies provided data and the quality of reporting and evidence is low. Limited data indicate the efficacy and adverse effects profiles of chlorpromazine and Penfluridol are generally similar. Penfluridol, however, may confer advantage by needing to be given only once per week. Firm conclusions are not possible without good-quality trials, and where these treatments are used, such trials are justified.
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chlorpromazine versus Penfluridol for schizophrenia
Cochrane Database of Systematic Reviews, 2017Co-Authors: Naemeh Nikvarz, Mostafa Vahedian, Navid KhaliliAbstract:Background The efficacy of chlorpromazine, a benchmark antipsychotic, has not been fully assessed in direct comparison with different individual antipsychotics. Penfluridol is another old antipsychotic with a long half-life so one oral dose may last up to one week. This could confer advantage. Objectives To assess the clinical effects of chlorpromazine compared with Penfluridol for adults with schizophrenia. Search methods On 31 March 2017, we searched the Cochrane Schizophrenia Group’s Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register. Selection criteria We included all randomised clinical trials focusing on chlorpromazine versus Penfluridol for adults with schizophrenia or related disorders. Outcomes of interest were death, service utilisation, global state, mental state, adverse effects and leaving the study early. We included trials meeting our selection criteria and reporting useable data. Data collection and analysis We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we planned to estimate the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE. Main results The review includes three studies with a total of 130 participants. Short-term results for hospital admissions showed no clear difference between chlorpromazine and Penfluridol (1 RCT, n = 29, RR 0.19, 95% CI 0.01 to 3.60, low-quality evidence). No clear difference in the incidence of akathisia was found at medium term (2 RCTs, n = 85, RR 0.19, 95% CI 0.04 to 1.06, low-quality evidence), and similar numbers of participants - nearly half - from each treatment group left the study early (3 RCTs, n = 130, RR 1.21, 95% CI 0.83 to 1.77, low-quality evidence). The risk of needing additional antiparkinsonian medication was less in the chlorpromazine group (2 RCTs, n = 74, RR 0.70, 95% CI 0.51 to 0.95). No useable data reported clinically important change in global or mental state. No data were reported for relapse. No deaths were reported by the trials. Authors' conclusions Only three small studies provided data and the quality of reporting and evidence is low. Limited data indicate the efficacy and adverse effects profiles of chlorpromazine and Penfluridol are generally similar. Penfluridol, however, may confer advantage by needing to be given only once per week. Firm conclusions are not possible without good-quality trials, and where these treatments are used, such trials are justified.