Niclosamide

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Wei Chen - One of the best experts on this subject based on the ideXlab platform.

  • Niclosamide induced wnt signaling inhibition in colorectal cancer is mediated by autophagy
    Biochemical Journal, 2019
    Co-Authors: Jiangbo Wang, Robert A. Mook, Richard T. Premont, Xiurong Ren, Hailan Piao, Shengli Zhao, Takuya Osada, Michael A Morse, H K Lyerly, Wei Chen
    Abstract:

    The Wnt signaling pathway, known for regulating genes critical to normal embryonic development and tissue homeostasis, is dysregulated in many types of cancer. Previously, we identified that the anthelmintic drug Niclosamide inhibited Wnt signaling by promoting internalization of Wnt receptor Frizzled 1 and degradation of Wnt signaling pathway proteins, Dishevelled 2 and β-catenin, contributing to suppression of colorectal cancer growth in vitro and in vivo Here, we provide evidence that Niclosamide-mediated inhibition of Wnt signaling is mediated through autophagosomes induced by Niclosamide. Specifically, Niclosamide promotes the co-localization of Frizzled 1 or β-catenin with LC3, an autophagosome marker. Niclosamide inhibition of Wnt signaling is attenuated in autophagosome-deficient ATG5-/- MEF cells or cells expressing shRNA targeting Beclin1, a critical constituent of autophagosome. Treatment with the autophagosome inhibitor 3MA blocks Niclosamide-mediated Frizzled 1 degradation. The sensitivity of colorectal cancer cells to growth inhibition by Niclosamide is correlated with autophagosome formation induced by Niclosamide. Niclosamide inhibits mTORC1 and ULK1 activities and induces LC3B expression in Niclosamide-sensitive cell lines, but not in the Niclosamide-resistant cell lines tested. Interestingly, Niclosamide is a less effective inhibitor of Wnt-responsive genes (β-catenin, c-Myc, and Survivin) in the Niclosamide-resistant cells than in the Niclosamide-sensitive cells, suggesting that deficient autophagy induction by Niclosamide compromises the effect of Niclosamide on Wnt signaling. Our findings provide a mechanistic understanding of the role of autophagosomes in the inhibition of Wnt signaling by Niclosamide and may provide biomarkers to assist selection of patients whose tumors are likely to respond to Niclosamide.

  • Niclosamide: Beyond an antihelminthic drug.
    Cellular signalling, 2017
    Co-Authors: Wei Chen, Robert A. Mook, Richard T. Premont, Jiangbo Wang
    Abstract:

    Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that Niclosamide may have broad clinical applications for the treatment of diseases other than those caused by parasites. These diseases and symptoms may include cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, and systemic sclerosis. Among the underlying mechanisms associated with the drug actions of Niclosamide are uncoupling of oxidative phosphorylation, and modulation of Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways. Here we provide a brief overview of the biological activities of Niclosamide, its potential clinical applications, and its challenges for use as a new therapy for systemic diseases.

  • benzimidazole inhibitors from the Niclosamide chemotype inhibit wnt β catenin signaling with selectivity over effects on atp homeostasis
    Bioorganic & Medicinal Chemistry, 2017
    Co-Authors: Robert A. Mook, Jiangbo Wang, Hailan Piao, Larry S Barak, Kim H Lyerly, Wei Chen
    Abstract:

    Abstract The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide’s mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol ( 4 ) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide’s inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

  • structure activity studies of wnt β catenin inhibition in the Niclosamide chemotype identification of derivatives with improved drug exposure
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Robert A. Mook, Jiangbo Wang, Minyong Chen, Ivan Spasojevic, Larry S Barak, Kim H Lyerly, Wei Chen
    Abstract:

    Abstract The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4′-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N -methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide’s low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32 ), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.

  • antihelminth compound Niclosamide downregulates wnt signaling and elicits antitumor responses in tumors with activating apc mutations
    Cancer Research, 2011
    Co-Authors: Takuya Osada, Wei Chen, Minyong Chen, Ivan Spasojevic, Xiao Yi Yang, Jeffrey Vandeusen, David S Hsu, Bryan M Clary, Timothy M Clay, Michael A Morse
    Abstract:

    Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound Niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether Niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that Niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered Niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition Niclosamide for the treatment of CRC.

Donald J Buchsbaum - One of the best experts on this subject based on the ideXlab platform.

  • Niclosamide analogs for treatment of ovarian cancer
    International Journal of Gynecological Cancer, 2015
    Co-Authors: Christen Walters L Haygood, Rebecca C Arend, Abhishek Gangrade, Somsundaram Chettiar, Nicholas Regan, Christopher J Hassmann, Bertha Hidalgo, J M Straughn, Donald J Buchsbaum
    Abstract:

    Objective Niclosamide has shown activity against ovarian cancer in vitro; however, it has low bioavailability in vivo. Therefore, we investigated the cytotoxicity of Niclosamide analogs in combination with carboplatin against ovarian cancer patient ascites cells and tissue slices. Materials/Methods Tumorspheres were isolated from ascites collected from patients undergoing ovarian cancer surgery and plated at 10,000 cells per 50 μL into low attachment plates. Tumor slices were also processed at the time of surgery. These were treated concurrently with Niclosamide or analogs (0.1–5 μM) and carboplatin (5–150 μM). At 48 hours, cell viability was assessed with ATPlite assay. Western blotting was used to determine expression of Wnt/β-catenin proteins in ascites cells. Results Cytotoxicity of Niclosamide and its analogs in combination with carboplatin was demonstrated in 24 patient ascites samples. Increased cytotoxicity was seen with 2 analogs in 23 patient ascites samples when compared with Niclosamide. Similar cytotoxicity was produced in an ex vivo tumor slice model. Western blot analysis showed decreased expression of Wnt/β-catenin proteins with Niclosamide and analog treatment in a dose-dependent fashion. Conclusions The Niclosamide-like analogs produced cytotoxicity both alone and in combination with carboplatin against tumorspheres from patient ascites and slices from solid tumor samples. Tumor slices showed similar cytotoxicity to matched ascites samples. Western blots showed down-regulation of Wnt pathway–associated proteins in patient samples treated with Niclosamide analogs. These results suggest that more soluble Niclosamide analogs may be useful for the treatment of ovarian cancer in combination with chemotherapy.

  • multi targeted therapy of cancer by Niclosamide a new application for an old drug
    Cancer Letters, 2014
    Co-Authors: Michael J Roberts, Rebecca C Arend, Rajeev S Samant, Donald J Buchsbaum
    Abstract:

    The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely Niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified Niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of Niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of Niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of Niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.

  • inhibition of wnt β catenin pathway by Niclosamide a therapeutic target for ovarian cancer
    Gynecologic Oncology, 2014
    Co-Authors: Rebecca C Arend, Bertha Hidalgo, Rajeev S Samant, Angelina I Londonojoshi, Michael G Conner, Ronald D Alvarez, Charles N Landen, Michael J Straughn, Donald J Buchsbaum
    Abstract:

    Objective. The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate Niclosamide as a potential therapeutic agent for ovarian cancer. Methods. Tumor cells isolated from 34 patients' ascites with primary ovarian cancer were treated with Niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with Niclosamide. Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. Conclusion. This study demonstrates that Niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other Niclosamide analogs as a treatment option for ovarian cancer.

Robert A. Mook - One of the best experts on this subject based on the ideXlab platform.

  • Niclosamide induced wnt signaling inhibition in colorectal cancer is mediated by autophagy
    Biochemical Journal, 2019
    Co-Authors: Jiangbo Wang, Robert A. Mook, Richard T. Premont, Xiurong Ren, Hailan Piao, Shengli Zhao, Takuya Osada, Michael A Morse, H K Lyerly, Wei Chen
    Abstract:

    The Wnt signaling pathway, known for regulating genes critical to normal embryonic development and tissue homeostasis, is dysregulated in many types of cancer. Previously, we identified that the anthelmintic drug Niclosamide inhibited Wnt signaling by promoting internalization of Wnt receptor Frizzled 1 and degradation of Wnt signaling pathway proteins, Dishevelled 2 and β-catenin, contributing to suppression of colorectal cancer growth in vitro and in vivo Here, we provide evidence that Niclosamide-mediated inhibition of Wnt signaling is mediated through autophagosomes induced by Niclosamide. Specifically, Niclosamide promotes the co-localization of Frizzled 1 or β-catenin with LC3, an autophagosome marker. Niclosamide inhibition of Wnt signaling is attenuated in autophagosome-deficient ATG5-/- MEF cells or cells expressing shRNA targeting Beclin1, a critical constituent of autophagosome. Treatment with the autophagosome inhibitor 3MA blocks Niclosamide-mediated Frizzled 1 degradation. The sensitivity of colorectal cancer cells to growth inhibition by Niclosamide is correlated with autophagosome formation induced by Niclosamide. Niclosamide inhibits mTORC1 and ULK1 activities and induces LC3B expression in Niclosamide-sensitive cell lines, but not in the Niclosamide-resistant cell lines tested. Interestingly, Niclosamide is a less effective inhibitor of Wnt-responsive genes (β-catenin, c-Myc, and Survivin) in the Niclosamide-resistant cells than in the Niclosamide-sensitive cells, suggesting that deficient autophagy induction by Niclosamide compromises the effect of Niclosamide on Wnt signaling. Our findings provide a mechanistic understanding of the role of autophagosomes in the inhibition of Wnt signaling by Niclosamide and may provide biomarkers to assist selection of patients whose tumors are likely to respond to Niclosamide.

  • Niclosamide: Beyond an antihelminthic drug.
    Cellular signalling, 2017
    Co-Authors: Wei Chen, Robert A. Mook, Richard T. Premont, Jiangbo Wang
    Abstract:

    Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that Niclosamide may have broad clinical applications for the treatment of diseases other than those caused by parasites. These diseases and symptoms may include cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, and systemic sclerosis. Among the underlying mechanisms associated with the drug actions of Niclosamide are uncoupling of oxidative phosphorylation, and modulation of Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways. Here we provide a brief overview of the biological activities of Niclosamide, its potential clinical applications, and its challenges for use as a new therapy for systemic diseases.

  • benzimidazole inhibitors from the Niclosamide chemotype inhibit wnt β catenin signaling with selectivity over effects on atp homeostasis
    Bioorganic & Medicinal Chemistry, 2017
    Co-Authors: Robert A. Mook, Jiangbo Wang, Hailan Piao, Larry S Barak, Kim H Lyerly, Wei Chen
    Abstract:

    Abstract The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide’s mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol ( 4 ) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide’s inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

  • structure activity studies of wnt β catenin inhibition in the Niclosamide chemotype identification of derivatives with improved drug exposure
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Robert A. Mook, Jiangbo Wang, Minyong Chen, Ivan Spasojevic, Larry S Barak, Kim H Lyerly, Wei Chen
    Abstract:

    Abstract The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4′-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N -methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide’s low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32 ), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.

Rebecca C Arend - One of the best experts on this subject based on the ideXlab platform.

  • Niclosamide analogs for treatment of ovarian cancer
    International Journal of Gynecological Cancer, 2015
    Co-Authors: Christen Walters L Haygood, Rebecca C Arend, Abhishek Gangrade, Somsundaram Chettiar, Nicholas Regan, Christopher J Hassmann, Bertha Hidalgo, J M Straughn, Donald J Buchsbaum
    Abstract:

    Objective Niclosamide has shown activity against ovarian cancer in vitro; however, it has low bioavailability in vivo. Therefore, we investigated the cytotoxicity of Niclosamide analogs in combination with carboplatin against ovarian cancer patient ascites cells and tissue slices. Materials/Methods Tumorspheres were isolated from ascites collected from patients undergoing ovarian cancer surgery and plated at 10,000 cells per 50 μL into low attachment plates. Tumor slices were also processed at the time of surgery. These were treated concurrently with Niclosamide or analogs (0.1–5 μM) and carboplatin (5–150 μM). At 48 hours, cell viability was assessed with ATPlite assay. Western blotting was used to determine expression of Wnt/β-catenin proteins in ascites cells. Results Cytotoxicity of Niclosamide and its analogs in combination with carboplatin was demonstrated in 24 patient ascites samples. Increased cytotoxicity was seen with 2 analogs in 23 patient ascites samples when compared with Niclosamide. Similar cytotoxicity was produced in an ex vivo tumor slice model. Western blot analysis showed decreased expression of Wnt/β-catenin proteins with Niclosamide and analog treatment in a dose-dependent fashion. Conclusions The Niclosamide-like analogs produced cytotoxicity both alone and in combination with carboplatin against tumorspheres from patient ascites and slices from solid tumor samples. Tumor slices showed similar cytotoxicity to matched ascites samples. Western blots showed down-regulation of Wnt pathway–associated proteins in patient samples treated with Niclosamide analogs. These results suggest that more soluble Niclosamide analogs may be useful for the treatment of ovarian cancer in combination with chemotherapy.

  • multi targeted therapy of cancer by Niclosamide a new application for an old drug
    Cancer Letters, 2014
    Co-Authors: Michael J Roberts, Rebecca C Arend, Rajeev S Samant, Donald J Buchsbaum
    Abstract:

    The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely Niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified Niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of Niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of Niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of Niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.

  • inhibition of wnt β catenin pathway by Niclosamide a therapeutic target for ovarian cancer
    Gynecologic Oncology, 2014
    Co-Authors: Rebecca C Arend, Bertha Hidalgo, Rajeev S Samant, Angelina I Londonojoshi, Michael G Conner, Ronald D Alvarez, Charles N Landen, Michael J Straughn, Donald J Buchsbaum
    Abstract:

    Objective. The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate Niclosamide as a potential therapeutic agent for ovarian cancer. Methods. Tumor cells isolated from 34 patients' ascites with primary ovarian cancer were treated with Niclosamide (0.1 to 5 μM) ± carboplatin (5 to 150 μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with Niclosamide. Results. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/β-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. Conclusion. This study demonstrates that Niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/β-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other Niclosamide analogs as a treatment option for ovarian cancer.

  • effect of Niclosamide on basal like breast cancers
    Molecular Cancer Therapeutics, 2014
    Co-Authors: Angelina I Londonojoshi, Rebecca C Arend, Bertha Hidalgo, Rajeev S Samant, Laura Aristizabal, Brandon J Metge, William E Grizzle, Michael B Conner, Andres Forerotorres, Albert F Lobuglio
    Abstract:

    Basal-like breast cancers (BLBC) are poorly differentiated and display aggressive clinical behavior. These tumors become resistant to cytotoxic agents, and tumor relapse has been attributed to the presence of cancer stem cells (CSC). One of the pathways involved in CSC regulation is the Wnt/β-catenin signaling pathway. LRP6, a Wnt ligand receptor, is one of the critical elements of this pathway and could potentially be an excellent therapeutic target. Niclosamide has been shown to inhibit the Wnt/β-catenin signaling pathway by causing degradation of LRP6. TRA-8, a monoclonal antibody specific to TRAIL death receptor 5, is cytotoxic to BLBC cell lines and their CSC-enriched populations. The goal of this study was to examine whether Niclosamide is cytotoxic to BLBCs, specifically the CSC population, and if in combination with TRA-8 could produce increased cytotoxicity. Aldehyde dehydrogenase (ALDH) is a known marker of CSCs. By testing BLBC cells for ALDH expression by flow cytometry, we were able to isolate a nonadherent population of cells that have high ALDH expression. Niclosamide showed cytotoxicity against these nonadherent ALDH-expressing cells in addition to adherent cells from four BLBC cell lines: 2LMP, SUM159, HCC1187, and HCC1143. Niclosamide treatment produced reduced levels of LRP6 and β-catenin, which is a downstream Wnt/β-catenin signaling protein. The combination of TRA-8 and Niclosamide produced additive cytotoxicity and a reduction in Wnt/β-catenin activity. Niclosamide in combination with TRA-8 suppressed growth of 2LMP orthotopic tumor xenografts. These results suggest that Niclosamide or congeners of this agent may be useful for the treatment of BLBC.

Jiangbo Wang - One of the best experts on this subject based on the ideXlab platform.

  • Niclosamide induced wnt signaling inhibition in colorectal cancer is mediated by autophagy
    Biochemical Journal, 2019
    Co-Authors: Jiangbo Wang, Robert A. Mook, Richard T. Premont, Xiurong Ren, Hailan Piao, Shengli Zhao, Takuya Osada, Michael A Morse, H K Lyerly, Wei Chen
    Abstract:

    The Wnt signaling pathway, known for regulating genes critical to normal embryonic development and tissue homeostasis, is dysregulated in many types of cancer. Previously, we identified that the anthelmintic drug Niclosamide inhibited Wnt signaling by promoting internalization of Wnt receptor Frizzled 1 and degradation of Wnt signaling pathway proteins, Dishevelled 2 and β-catenin, contributing to suppression of colorectal cancer growth in vitro and in vivo Here, we provide evidence that Niclosamide-mediated inhibition of Wnt signaling is mediated through autophagosomes induced by Niclosamide. Specifically, Niclosamide promotes the co-localization of Frizzled 1 or β-catenin with LC3, an autophagosome marker. Niclosamide inhibition of Wnt signaling is attenuated in autophagosome-deficient ATG5-/- MEF cells or cells expressing shRNA targeting Beclin1, a critical constituent of autophagosome. Treatment with the autophagosome inhibitor 3MA blocks Niclosamide-mediated Frizzled 1 degradation. The sensitivity of colorectal cancer cells to growth inhibition by Niclosamide is correlated with autophagosome formation induced by Niclosamide. Niclosamide inhibits mTORC1 and ULK1 activities and induces LC3B expression in Niclosamide-sensitive cell lines, but not in the Niclosamide-resistant cell lines tested. Interestingly, Niclosamide is a less effective inhibitor of Wnt-responsive genes (β-catenin, c-Myc, and Survivin) in the Niclosamide-resistant cells than in the Niclosamide-sensitive cells, suggesting that deficient autophagy induction by Niclosamide compromises the effect of Niclosamide on Wnt signaling. Our findings provide a mechanistic understanding of the role of autophagosomes in the inhibition of Wnt signaling by Niclosamide and may provide biomarkers to assist selection of patients whose tumors are likely to respond to Niclosamide.

  • Niclosamide: Beyond an antihelminthic drug.
    Cellular signalling, 2017
    Co-Authors: Wei Chen, Robert A. Mook, Richard T. Premont, Jiangbo Wang
    Abstract:

    Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that Niclosamide may have broad clinical applications for the treatment of diseases other than those caused by parasites. These diseases and symptoms may include cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, and systemic sclerosis. Among the underlying mechanisms associated with the drug actions of Niclosamide are uncoupling of oxidative phosphorylation, and modulation of Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways. Here we provide a brief overview of the biological activities of Niclosamide, its potential clinical applications, and its challenges for use as a new therapy for systemic diseases.

  • benzimidazole inhibitors from the Niclosamide chemotype inhibit wnt β catenin signaling with selectivity over effects on atp homeostasis
    Bioorganic & Medicinal Chemistry, 2017
    Co-Authors: Robert A. Mook, Jiangbo Wang, Hailan Piao, Larry S Barak, Kim H Lyerly, Wei Chen
    Abstract:

    Abstract The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide’s mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol ( 4 ) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide’s inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

  • structure activity studies of wnt β catenin inhibition in the Niclosamide chemotype identification of derivatives with improved drug exposure
    Bioorganic & Medicinal Chemistry, 2015
    Co-Authors: Robert A. Mook, Jiangbo Wang, Minyong Chen, Ivan Spasojevic, Larry S Barak, Kim H Lyerly, Wei Chen
    Abstract:

    Abstract The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4′-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N -methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide’s low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32 ), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.