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Schematic representation of the drug screening procedure. A total of 1,301 compounds from five libraries were
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Glioma stem cell (GSC)-targeted therapy is expected to be one of the most innovative approaches to treat patients with glioblastoma (GBM). A number of the drugs that restrain the signaling pathway essential for GSC maintenance have been under clinical trials. Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting age...
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... the 1,301 compounds screened, 89 compounds showed various degrees of viability inhibition of GSCs, as determined by the WST-8 cell proliferation assay during initial screening (Figure 1). After we excluded screened by a three-step procedure. First, compounds (1, 5, 20 μM) exhibiting 25% or more reduction in the cell viability, measured by the WST-8 assay, were selected. Second, drugs with an already reported therapeutic potential against GBM or those under clinical trials were excluded. Third, drugs attenuating the cell viability and sphere-forming capacity at lower concentrations (0.2, 0.5, 1 μM) were selected. Some examples showing efficacy or inefficacy of 1st screening were presented in the right panels. the drugs that are under clinical trials for GBM or have already been reported to show effects on GBM cells, 36 compounds were identified during a second round of screening. Among those, three drugs were selected, which exhibited strong inhibitory effects on the GBM cell viability at lower concentrations (Figure 1). Of the 3 compounds, fluspirilene (8-[4,4-bis(4-fluorophenyl) butyl]-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one) was selected because of its novelty and efficacy in the treatment of GBM cells (Figure 1) and the ability to penetrate blood-brain barrier (BBB) [21]. Fluspirilene is a potent diphenylbutylpiperidine antipsychotic drug that has been used for the treatment of schizophrenia for many years. The other two compounds are being investigated as next ...
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... the 1,301 compounds screened, 89 compounds showed various degrees of viability inhibition of GSCs, as determined by the WST-8 cell proliferation assay during initial screening (Figure 1). After we excluded screened by a three-step procedure. First, compounds (1, 5, 20 μM) exhibiting 25% or more reduction in the cell viability, measured by the WST-8 assay, were selected. Second, drugs with an already reported therapeutic potential against GBM or those under clinical trials were excluded. Third, drugs attenuating the cell viability and sphere-forming capacity at lower concentrations (0.2, 0.5, 1 μM) were selected. Some examples showing efficacy or inefficacy of 1st screening were presented in the right panels. the drugs that are under clinical trials for GBM or have already been reported to show effects on GBM cells, 36 compounds were identified during a second round of screening. Among those, three drugs were selected, which exhibited strong inhibitory effects on the GBM cell viability at lower concentrations (Figure 1). Of the 3 compounds, fluspirilene (8-[4,4-bis(4-fluorophenyl) butyl]-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one) was selected because of its novelty and efficacy in the treatment of GBM cells (Figure 1) and the ability to penetrate blood-brain barrier (BBB) [21]. Fluspirilene is a potent diphenylbutylpiperidine antipsychotic drug that has been used for the treatment of schizophrenia for many years. The other two compounds are being investigated as next ...
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... the 1,301 compounds screened, 89 compounds showed various degrees of viability inhibition of GSCs, as determined by the WST-8 cell proliferation assay during initial screening (Figure 1). After we excluded screened by a three-step procedure. First, compounds (1, 5, 20 μM) exhibiting 25% or more reduction in the cell viability, measured by the WST-8 assay, were selected. Second, drugs with an already reported therapeutic potential against GBM or those under clinical trials were excluded. Third, drugs attenuating the cell viability and sphere-forming capacity at lower concentrations (0.2, 0.5, 1 μM) were selected. Some examples showing efficacy or inefficacy of 1st screening were presented in the right panels. the drugs that are under clinical trials for GBM or have already been reported to show effects on GBM cells, 36 compounds were identified during a second round of screening. Among those, three drugs were selected, which exhibited strong inhibitory effects on the GBM cell viability at lower concentrations (Figure 1). Of the 3 compounds, fluspirilene (8-[4,4-bis(4-fluorophenyl) butyl]-1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one) was selected because of its novelty and efficacy in the treatment of GBM cells (Figure 1) and the ability to penetrate blood-brain barrier (BBB) [21]. Fluspirilene is a potent diphenylbutylpiperidine antipsychotic drug that has been used for the treatment of schizophrenia for many years. The other two compounds are being investigated as next ...
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... used the following five SCREEN-WELL® libraries from Enzo Life Sciences (Farmingdale, NY, USA): 1) FDA (U.S. Food and Drug Administration)-approved drug library (640 compounds; CB-BML-2841J0100); 2) ICCB (Harvard Institute of Chemistry and Cell Biology) known bioactives library (480 compounds; CB-BML- 2840J0100); 3) kinase inhibitor library (80 compounds; CB-BML-2832J0100); 4) fatty acid library (68 compounds; CB-BML-2803J0100); and 5) phosphatase inhibitor library (33 compounds; CB-BML-2834J0100). To identify effective compounds among the 1,301 compounds, three-step screening was performed (Figure 1). First, the three GSC lines (TGS01, TGS04, and KGS01) were treated with each compound provided in the libraries at three concentrations (1, 5, and 20 μM) in a 384-well plate (Corning, Cambridge, MA, USA) for 48 h, followed by a 2-(2-methoxy-4-nitrophenyl)- 3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-8) cell viability assay as described below. Compounds exhibiting 25% or more reduction in cell viability in a dose- dependent manner were selected. Second, drugs that have already been reported to have a therapeutic potential against GBM or those in clinical trials were excluded. Third, the WST-8 assay and sphere-forming assay were performed using the three GSC lines with lower concentrations (0.2, 0.5, and 1 μM) of the selected compounds. Candidate drugs were identified as demonstrating remarkable inhibition of cell viability even at the lowest ...
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... on the results of the in vitro study and following an institutional review board-approved protocol, we conducted an in vivo tumor-forming assay. The tumor histology of our animal model demonstrated several features characteristic of host GBM, including a highly proliferative and invasive nature (Supplementary Figure 1B). The number of diffusely infiltrating satellite lesions that were stained positive for nestin significantly decreased in the fluspirilene-treated mice ( Figure 6A). 2.5, and 5 μM, and viability curves of GBM cell lines were analyzed in the presence and absence of fluspirilene. The plate was read on a plate reader at the indicated time points. (B and C) Cells were treated with fluspirilene at 1.5 and 3 μM. Cells invading through a Matrigel-coated Transwell chamber were scored in the presence and absence of fluspirilene for 8 h. The mean numbers of cells and standard deviations were calculated for eight high-power microscopic fields. * p < 0.05, ** p < ...
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... human patient-derived GBM cell lines, TGS01 and TGS04 were established at University of Tokyo [62], and KGS01 was established at Kanazawa University. The use of these human materials and the protocols were approved by the Ethics Committees of Kanazawa University and University of Tokyo. TGS01 and TGS04 have already been confirmed as tumor- initiating cells since cultured cells have the self-renewal ability in vitro and recapitulate the original tumor in a mouse xenograft model [62]. KGS01 was also confirmed as a GSC line. Briefly, KGS01 had the ability to form spheres and express surface markers characteristic of stemness, such as CD133 [1], CD44 [63], and nestin [64,65] (Supplementary Figure 1A). KGS01 could differentiate into glial fibrillary acidic protein (GFAP)- and oligodendrocyte transcription factor (Olig2)-positive astrocyte-like cells as well as into neuron-specific class III beta-tubulin (Tuj1)-positive neuron-like cells in DMEM supplemented with 10% FBS (Supplementary Figure 1A) and grow into brain tumor, histologically recapitulating features of the original in vivo GBM (Supplementary Figure 1B). These cells were cultured in neurosphere medium containing DMEM/F12 (Gibco, Life Technologies, Carlsbad, CA, USA) supplemented with recombinant human EGF at 20 ng/mL (Sigma-Aldrich, St. Louis, MO, USA), recombinant human basic fibroblast growth factor at 20 ng/mL (Sigma-Aldrich), B27 supplement without vitamin A (Gibco), and GlutaMAX (Gibco). ...
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... human patient-derived GBM cell lines, TGS01 and TGS04 were established at University of Tokyo [62], and KGS01 was established at Kanazawa University. The use of these human materials and the protocols were approved by the Ethics Committees of Kanazawa University and University of Tokyo. TGS01 and TGS04 have already been confirmed as tumor- initiating cells since cultured cells have the self-renewal ability in vitro and recapitulate the original tumor in a mouse xenograft model [62]. KGS01 was also confirmed as a GSC line. Briefly, KGS01 had the ability to form spheres and express surface markers characteristic of stemness, such as CD133 [1], CD44 [63], and nestin [64,65] (Supplementary Figure 1A). KGS01 could differentiate into glial fibrillary acidic protein (GFAP)- and oligodendrocyte transcription factor (Olig2)-positive astrocyte-like cells as well as into neuron-specific class III beta-tubulin (Tuj1)-positive neuron-like cells in DMEM supplemented with 10% FBS (Supplementary Figure 1A) and grow into brain tumor, histologically recapitulating features of the original in vivo GBM (Supplementary Figure 1B). These cells were cultured in neurosphere medium containing DMEM/F12 (Gibco, Life Technologies, Carlsbad, CA, USA) supplemented with recombinant human EGF at 20 ng/mL (Sigma-Aldrich, St. Louis, MO, USA), recombinant human basic fibroblast growth factor at 20 ng/mL (Sigma-Aldrich), B27 supplement without vitamin A (Gibco), and GlutaMAX (Gibco). ...
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... human patient-derived GBM cell lines, TGS01 and TGS04 were established at University of Tokyo [62], and KGS01 was established at Kanazawa University. The use of these human materials and the protocols were approved by the Ethics Committees of Kanazawa University and University of Tokyo. TGS01 and TGS04 have already been confirmed as tumor- initiating cells since cultured cells have the self-renewal ability in vitro and recapitulate the original tumor in a mouse xenograft model [62]. KGS01 was also confirmed as a GSC line. Briefly, KGS01 had the ability to form spheres and express surface markers characteristic of stemness, such as CD133 [1], CD44 [63], and nestin [64,65] (Supplementary Figure 1A). KGS01 could differentiate into glial fibrillary acidic protein (GFAP)- and oligodendrocyte transcription factor (Olig2)-positive astrocyte-like cells as well as into neuron-specific class III beta-tubulin (Tuj1)-positive neuron-like cells in DMEM supplemented with 10% FBS (Supplementary Figure 1A) and grow into brain tumor, histologically recapitulating features of the original in vivo GBM (Supplementary Figure 1B). These cells were cultured in neurosphere medium containing DMEM/F12 (Gibco, Life Technologies, Carlsbad, CA, USA) supplemented with recombinant human EGF at 20 ng/mL (Sigma-Aldrich, St. Louis, MO, USA), recombinant human basic fibroblast growth factor at 20 ng/mL (Sigma-Aldrich), B27 supplement without vitamin A (Gibco), and GlutaMAX (Gibco). ...
Citations
... Furthermore, it directly regulates CSC biomarkers such as OCT4, Nanog and Sox2, decreasing CSC characteristics and inhibiting tumor growth. Dong et al. [71] found that the traditional antipsychotic drug fluspirilene can be utilized as a targeted treatment for GSCs. It works by inhibiting the STAT3-related signaling pathway, thereby reducing the proliferation of GSCs and their stemness, ultimately treating GBM. ...
... To date, the impact of CSC on mental illness in the nervous system has not been confirmed. Previous studies have reported that antipsychotic drugs might be able to treat CSC through pathways such as STAT3 and Akt, inhibiting the proliferation and spread of cancer cells [70,71]. However, the effects of these drugs on different types of tumors and CSCs may vary. ...
Cancer stem cells (CSCs) have been increasingly recognized in recent years. CSCs from human neural tumors are one of the root causes of metastatic tumor progression, therapeutic resistance and recurrence. However, there is a lack of comprehensive literature that systematically consolidates the biomarkers specific to CSCs in neurological cancers. Therefore, this review provides a comprehensive summary of cancer stem cell (CSC) biomarkers for neurological tumors such as glioma, meningioma, medulloblastoma and neurofibroma. It also points out the possible functions of these biomarkers in diagnosis, treatment and prognosis, providing a broader perspective. First, we quantitatively screened key words such as CSCs, biomarkers, and expression by bibliometric analysis and clarified the intrinsic connections between the key words. Then, we describe the CSC biomarkers of major neurological tumors and their pathway mechanisms, and provide an in-depth analysis of the commonalities and differences with the biomarkers of non-CSCs. In addition, many studies have shown that antipsychotic drugs can inhibit tumor growth and reduce the expression of CSC biomarkers, which facilitates targeted therapy against tumors in the nervous system. Therefore, this study will focus on the biomarkers of CSCs in the nervous system, hoping to provide guidance for future in-depth exploration and monitoring of neurological tumors for clinical applications.
... Accumulating lines of evidence have underscored the potential of repurposing antipsychotics as cancer therapeutics [39]. Particularly, based on their advantage to pass through the blood-brain barrier (BBB), typical antipsychotic drugs such as Chlorpromazine, Fluspirilene, Haloperidol, Penfluridol, Pimozide, and Trifluoperazine have been proven effective against glioblastoma (GBM) [40][41][42][43][44][45]. Besides brain tumors, the antitumor effects of these antipsychotics have been demonstrated on assorted types of malignancies, including breast cancer, colorectal cancer, liver cancer, lung cancer, oral cancer, pancreatic cancer, and prostate cancer [39 and the references therein]. ...
... Accumulating lines of evidence have underscored the potential of repurposing antipsychotics as cancer therapeutics [39]. Particularly, based on their advantage to pass through the blood-brain barrier (BBB), typical antipsychotic drugs such as Chlorpromazine, Fluspirilene, Haloperidol, Penfluridol, Pimozide, and Trifluoperazine have been proven effective against glioblastoma (GBM) [40][41][42][43][44][45]. Besides brain tumors, the antitumor effects of these antipsychotics have been demonstrated on assorted types of malignancies, including breast cancer, colorectal cancer, liver cancer, lung cancer, oral cancer, pancreatic cancer, and prostate cancer [39] and the references therein. ...
Bladder cancer is the leading urinary tract malignancy. Epidemiological evidence has linked lower cancer incidence in schizophrenia patients to long-term medication, highlighting the anticancer potential of antipsychotics. Sertindole is an atypical antipsychotic agent with reported anticancer action on breast and gastric cancers. Yet, sertindole's effect on bladder cancer remains unaddressed. We herein present the first evidence of sertindole's antiproliferative effect and mechanisms of action on human bladder cancer cells. Sertindole was cytotoxic against bladder cancer cells while less cytotoxic to normal urothelial cells. Apoptosis was a primary cause of sertindole's cytotoxicity, as the pan-caspase inhibitor z-VAD-fmk rescued cells from sertindole-induced killing. Mechanistically, sertindole inhibited the activation of signal transducer and activator of transcription 3 (STAT3), an oncogenic driver of bladder cancer, as sertindole lowered the levels of tyrosine 705-phosphorylated STAT3 along with that of STAT3's target gene BCL-xL. Notably, ectopic expression of the dominant-active STAT3 mutant impaired sertindole-induced apoptosis in addition to restoring BCL-xL expression. Moreover, bladder cancer cells overexpressing BCL-xL were refractory to sertindole's proapoptotic action, arguing that sertindole represses STAT3 to downregulate BCL-xL, culminating in the induction of apoptosis. Overall, the current study indicated sertindole exerts bladder cancer cytotoxicity by provoking apoptosis through targeted inhibition of the antiapoptotic STAT3/BCL-xL signaling axis. These findings implicate the potential to repurpose sertindole as a therapeutic strategy for bladder cancer.
... Previously, we and others identified several compounds that had some therapeutic effects on glioma. 9,[13][14][15][16][17] However, none of them have been applied to current clinical treatments. 18,19 Pentamidine, an antiprotozoal drug for pneumonia caused by Pneumocystis jirovecii, suppresses glucose metabolism, amino acid transport, and RNA synthesis. ...
... Previous reports have confirmed these cell lines as tumor-initiating cells, as cultured cells have self-renewal ability in vitro and recapitulate the original tumor in a mouse xenograft model. 9,24,25 These GICs were cultured as previously described. 9,25 Human GBM cell lines A172, T98G, and U87, were purchased from the European Collection of Cell Culture and were cultured as previously described. ...
... 9,24,25 These GICs were cultured as previously described. 9,25 Human GBM cell lines A172, T98G, and U87, were purchased from the European Collection of Cell Culture and were cultured as previously described. 26 In this study, we established differentiated KGS01 (dKGS01) and differentiated KGS07 (dKGS07). ...
Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.
... This traditional antipsychotic drug also showed anti-glioma stem cell activity based on in vitro and in vivo experiments. 53 The ...
... These screened small drugs possess inhibition potential against a plethora of diseases and antiviral activities are well-reported. 44,45,47,53 Therefore, these small drugs may be utilized to develop effective antiviral therapy against Mpox after validation in wet lab. ...
Mpox (formerly Monkeypox), a zoonotic illness caused by the Mpox virus, belongs to the Orthopoxvirus genus in the family Poxviridae. To design and develop effective antiviral therapeutics against DNA viruses, the DNA-dependent RNA polymerase (DdRp) of poxviruses has emerged as a promising drug target. In the present study, we modeled the three-dimensional (3D) structure of DdRp using a template-based homology approach. After modeling, virtual screening was performed to probe the molecular interactions between 1755 Food and Drug Administration-approved small molecule drugs (≤500 molecular weight) and the DdRp of Mpox. Based on the binding affinity and molecular interaction patterns, five drugs, lumacaftor (-11.7 kcal/mol), conivaptan (-11.7 kcal/mol), betulinic acid (-11.6 kcal/mol), fluspirilene (-11.3 kcal/mol), and imatinib (-11.2 kcal/mol), have been ranked as the top drug compounds interacting with Mpox DdRp. Complexes of these shortlisted drugs with DdRp were further evaluated using state-of-the-art all-atoms molecular dynamics (MD) simulations on 200 nanoseconds followed by principal component analysis (PCA). MD simulations and PCA results revealed highly stable interactions of these small drugs with DdRp. After due validation in wet-lab using available in vitro and in vivo experiments, these repurposed drugs can be further utilized for the treatment of contagious Mpox virus. The outcome of this study may establish a solid foundation to screen repurposed and natural compounds as potential antiviral therapeutics against different highly pathogenic viruses.
... Glioma is composed of heterogeneous cell populations, some of which are glioma initiating cells (GICs), which have the ability to self-renew and differentiate [8,9]. Previous studies have revealed that GICs play an important role in glioma invasion, and xenograft models using GICs, which were established from patient tumor tissue, sustained their invasive nature [10][11][12]. ...
A major malignant trait of gliomas is their remarkable infiltration capacity. When glioma develops, the tumor cells have already reached the distant part. Therefore, complete removal of the glioma is impossible. Recently, research on the involvement of the tumor microenvironment in glioma invasion has advanced. Local hypoxia triggers cell migration as an environmental factor. The transcription factor hypoxia-inducible factor (HIF) -1α, produced in tumor cells under hypoxia, promotes the transcription of various invasion related molecules. The extracellular matrix surrounding tumors is degraded by proteases secreted by tumor cells and simultaneously replaced by an extracellular matrix that promotes infiltration. Astrocytes and microglia become tumor-associated astrocytes and glioma-associated macrophages/microglia, respectively, in relation to tumor cells. These cells also promote glioma invasion. Interactions between glioma cells actively promote infiltration of each other. Surgery, chemotherapy, and radiation therapy transform the microenvironment, allowing glioma cells to invade. These findings indicate that the tumor microenvironment may be a target for glioma invasion. On the other hand, because the living body actively promotes tumor infiltration in response to the tumor, it is necessary to reconsider whether the invasion itself is friend or foe to the brain.
... Drug repositioning, or identifying and developing new uses of existing drugs, is a promising method used in the pharmaceutical industry to reduce the cost of developing new therapeutical drugs [56]. Our group [25], as well as others [57], performed drug repositioning to identify candidate drugs for use against glioblastomas and other brain tumors [58]. Specifically, antibiotics have gained considerable interest in drug repurposing for cancer therapy [59]. ...
Simple Summary
Given the significant costs and lengthy timelines of drug development and clinical trials, drug repositioning is a promising alternative to find effective treatments for brain tumors quickly and inexpensively. In the present study, using a simple drug screen of macrolides, we found that clindamycin (CLD) had cytotoxic effects on glioblastoma (GBM) cells. Further studies showed the inhibition of the mammalian target of rapamycin (mTOR) pathway as the key mechanism of action. Interestingly, we found that co-treatment with temozolomide (TMZ), the alkylating agent considered as standard therapy in GBM, enhanced these effects and proposed the inhibition of O6-methylguanine-DNA methyltransferase (MGMT) protein by CLD as a potential mechanism for this combination effect.
Abstract
Multimodal therapy including surgery, radiation treatment, and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to examine the signal activation patterns in GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose-dependent manner. These effects on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of the O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1)-positive cells within the tumor. These results suggest that CLD suppressed GBM cell growth by inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.
... Indeed, CPZ reduces cloning efficiency, neurosphere formation and downregulates the expression of stemness genes in neurospheres in GBM [87]. Fluspirilene suppresses proliferation and invasion in both GSCs (neurospheres) and GBM cells, acting via STAT3 inhibition [116]. STAT3 is a factor strongly connected with stemness, mesenchymal phenotype and resistance to RT and chemotherapy [117][118][119], which is also implied in cancer-driven immunosuppression [120]. ...
Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.
... Drug repositioning, or identifying and developing new uses of existing drugs, is a promising method used in the pharmaceutical industry to reduce the cost of developing new therapeutical drugs [50]. Our group [25] as well as others [51] have performed drug repositioning to identify candidate drugs glioblastomas and other brain tumors [52]. Specifically, anti-biotics have gained considerable interest in drug repurposing for cancer therapy [53]. ...
Multimodal therapy including surgery, radiation treatment and temozolomide (TMZ) is performed on glioblastoma (GBM). However, the prognosis is still poor and there is an urgent need to develop effective treatments to improve survival. Molecular biological analysis was conducted to exam-ine the signal activation patterns at GBM specimens and remains an open problem. Advanced macrolides, such as azithromycin, reduce the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K), a downstream mammalian target of rapamycin (mTOR) effector, and suppress the proliferation of T-cells. We focused on its unique profile and screened for the antitumor activity of approved macrolide antibiotics. Clindamycin (CLD) reduced the viability of GBM cells in vitro. We assessed the effects of the candidate macrolide on the mTOR pathway through Western blotting. CLD attenuated p70S6K phosphorylation in a dose dependent manner. These effects of on GBM cells were enhanced by co-treatment with TMZ. Furthermore, CLD inhibited the expression of O6-methylguanine-DNA methyltransferase (MGMT) protein in cultured cells. In the mouse xenograft model, CLD and TMZ co-administration significantly suppressed the tumor growth and markedly decreased the number of Ki-67 (clone MIB-1) positive cells within the tumor. These results suggest that CLD suppresses GBM cell growth by the inhibiting mTOR signaling. Moreover, CLD and TMZ showed promising synergistic antitumor activity.
... Of note, the inhibition of STAT-3 was observed in both glioma stem cells and differentiated glioma cells. Subsequently, the drug was tested in vivo, leading to significant tumor reduction (p = 0.017) and life prolongation (p = 0.026) in mice xenografted with cells with similar characteristics to GBM cells [72]. Finally, Patil et al., based on their own in vitro studies, proposed that FSP acts as a p53-MDM2 inhibitor by binding to the p-53 binding pocket of the MDM2 protein, causing activation of the tumor suppressor protein p53 and subsequent inhibition of tumor growth in human colon cells and several other human tumor cell lines in the NCI60 cell line panel [73]. ...
Cancer is a leading cause of death worldwide, with approximately 19 million new cases each year. Lately, several novel chemotherapeutic drugs have been introduced, efficiently inhibiting tumor growth and proliferation. However, developing a new drug is a time- and money-consuming process, requiring around 1 billion dollars and nearly ten years, with only a minority of the initially effective anti-cancer drugs experimentally finally being efficient in human clinical trials. Drug repurposing for cancer treatment is an optimal alternative as the safety of these drugs has been previously tested, and thus, in case of successful preclinical studies, can be introduced faster and with a lower cost into phase 3 clinical trials. Antipsychotic drugs are associated with anti-cancer properties and, lately, there has been an increasing interest in their role in cancer treatment. In the present review, we discussed in detail the in-vitro and in-vivo properties of the most common typical and atypical antipsychotics, along with their mechanism of action.
... Fluspirilene and penfluridol, both first-generation diphenylbutylpiperidine antipsychotics, were also found to impair GSC function [52,53]. Fluspirilene inhibited STAT3, resulting in decreased GBM proliferation, invasion and tumor growth, penfluridol decreased colony sphere number and size with reductions in (sex determining region Y)-box 2 (SOX2) and octamer-binding transcription factor 4 (OCT4) [52,53]. ...
... Fluspirilene and penfluridol, both first-generation diphenylbutylpiperidine antipsychotics, were also found to impair GSC function [52,53]. Fluspirilene inhibited STAT3, resulting in decreased GBM proliferation, invasion and tumor growth, penfluridol decreased colony sphere number and size with reductions in (sex determining region Y)-box 2 (SOX2) and octamer-binding transcription factor 4 (OCT4) [52,53]. Additionally, penfluridol decreased migration through integrin interference and uPAR reduction and blocked EMT by attenuating ZEB1 expression. ...
Simple Summary
Glioblastoma is a devastating malignancy that has continued to prove resistant to a variety of therapeutics. No new systemic therapy has been approved for use against glioblastoma in almost two decades. This observation is particularly disturbing given the amount of money invested in identifying novel therapies for this disease. A relatively rapid and economical pipeline for identification of novel agents is drug repurposing. Here, a comprehensive review detailing the state of drug repurposing in glioblastoma is provided. We reveal details on studies that have examined agents in vitro, in animal models and in patients. While most agents have not progressed beyond the initial stages, several drugs, from a variety of classes, have demonstrated promising results in early phase clinical trials.
Abstract
The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In ad-dition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of the literature and clinical trials provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is pos-sible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies.
