The Experts below are selected from a list of 648 Experts worldwide ranked by ideXlab platform
Riyaz Basha - One of the best experts on this subject based on the ideXlab platform.
-
copper Tolfenamic Acid evaluation of stability and anti cancer activity
Investigational New Drugs, 2019Co-Authors: Myrna Hurtado, Umesh T Sankpal, Jaya Chhabra, Deondra T Brown, Rajasekhar Maram, Rafid Patel, Raj K Gurung, Jerry W Simecka, Alvin A Holder, Riyaz BashaAbstract:The non-steroidal anti-inflammatory drug, Tolfenamic Acid (TA) acts as an anti-cancer agent in several adult and pediatric cancer models. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, [Cu(TA)2(bpy)] (Cu-TA) has been synthesized in order to enhance therapeutic activity. In this study, we synthesized Cu-TA using an established method, characterized it by UV visible spectroscopy and Fourier-transform infrared spectroscopy (FTIR), and tested its anti-cancer activity using twelve cell lines representing various cancers, such as Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, pancreatic and prostate. The anti-proliferative activity of Cu-TA was determined at 48 h post-treatment and compared with the parental compound, TA. The IC50 values were calculated using GraphPad Prism software. The biological stability of Cu-TA was evaluated using twelve-month-old powder and six-month-old stock solution. Cardiomyocytes (H9C2) were used to test the cytotoxicity in non-malignant cells. Cu-TA showed higher anti-proliferative activity, and the IC50 values were 30 to 80% lower when compared with TA. H9C2 cells were non-responsive to Cu-TA, suggesting that it is selective towards malignant cells. Comparison of the twelve-month-old powder and six-month-old stock solution using the Panc1 cell line showed similar IC50 values (<5% variation), confirming the stability of Cu-TA either in powder or solution form. These findings demonstrate the potential of Cu-TA as an effective anti-cancer agent. Further studies to delineate the detailed mechanism of action of Cu-TA for specific cancer model are underway.
-
Tolfenamic Acid induced alterations in genes and pathways in pancreatic cancer cells
Oncotarget, 2017Co-Authors: Umesh T Sankpal, Steve Goodison, Michelle Jonespauley, Myrna Hurtado, Fan Zhang, Riyaz BashaAbstract:// Umesh T. Sankpal 1 , Steve Goodison 2 , Michelle Jones-Pauley 1 , Myrna Hurtado 3 , Fan Zhang 3 , Riyaz Basha 1, 3 1 Texas College of Osteopathic Medicine, University of North Texas Health Science Center, TX, USA 2 Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA 3 Institute for Molecular Medicine, University of North Texas Health Science Center, TX, USA Correspondence to: Riyaz Basha, email: riyaz.basha@unthsc.edu Keywords: Tolfenamic Acid, pancreatic cancer, Sp1, microarray analysis Received: November 04, 2016 Accepted: January 05, 2017 Published: January 14, 2017 ABSTRACT Non-steroidal anti-inflammatory drugs (NSAIDs) are being tested extensively for their role in the treatment and prevention of several cancers. Typically NSAIDs exhibit anti-tumor activities via modulation of cyclooxygenase (COX)-dependent mechanisms, however, an anti-cancer NSAID Tolfenamic Acid (TA) is believed to work through COX-independent pathways. Results from our laboratory and others have demonstrated the anti-cancer activity of TA in various cancer models including pancreatic cancer. TA has been shown to modulate certain cellular processes including, apoptosis, reactive oxygen species and signaling. In this study, molecular profiling was performed to precisely understand the mode of action of TA. Three pancreatic cancer cell lines, L3.6pl, MIA PaCa-2, and Panc1 were treated with TA (50 μM for 48 h) and the changes in gene expression was evaluated using the Affymetrix GeneChip Human Gene ST Array platform. Microarray results were further validated using quantitative PCR for seven genes altered by TA treatment in all three cell lines. Functional analysis of differentially expressed genes (2 fold increase or decrease, p < 0.05) using Ingenuity Pathway Analysis software, revealed that TA treatment predominantly affected the genes involved in cell cycle, cell growth and proliferation, and cell death and survival. Promoter analysis of the differentially expressed genes revealed that they are enriched for Sp1 binding sites, suggesting that Sp1 could be a major contributor in mediating the effect of TA. The gene expression studies identified new targets involved in TA’s mode of action, while supporting the hypothesis about the association of Sp1 in TA mediated effects in pancreatic cancer.
-
abstract 2544 combination of anti cancer small molecule Tolfenamic Acid and curcumin effectively inhibits colon cancer cell growth
Cancer Research, 2015Co-Authors: Umesh T Sankpal, Myrna Hurtado, Ganji Purnachandra Nagaraju, Sriharika R Gottipolu, Bassel F Elrayes, Mamoru Shoji, Christopher G Jordan, Riyaz BashaAbstract:Tolfenamic Acid (TA) is small molecule and non-steroidal anti-inflammatory drug which is known to inhibit human cancer cells and mouse tumor growth in some cancer models. TA is known to target the transcription factor, specificity protein1 (Sp1), that mediates the expression of several genes associated with cancer, including survivin, a key member of the inhibitor of apoptosis proteins (IAP) family. Curcumin is an aromatic constituent of the plant curcuma longa (turmeric) which is extensively studied in some malignancies including breast, pancreatic and colon cancers. Even though curcumin shows a broad spectrum of anti-cancer activity in pre-clinical studies, its clinical application is greatly affected by its low bioavailability. Hence, several strategies to improve the therapeutic response of curcumin are being pursued, including the synthesis of curcumin analogs and using curcumin in combination with other small molecules or drugs to increase bioavailability. In this study, using a colon cancer model, the therapeutic efficacy of curcumin and a curcumin analog EF31 in combination with an anti-cancer small molecule TA was evaluated. Colon cancer cell lines HCT116, HT29, and SW620 were treated with TA, curcumin, or EF31 and cell viability was measured at 24, 48, and 72 hours post-treatment. All agents showed a steady and consistent decrease in cell viability, following a clear dose and time-dependent response. Combination of TA with curcumin or EF31 showed higher growth inhibition compared to single agent treatment. Analysis of apoptosis was carried out to determine the mode of growth inhibition, using flow cytometry (JC-1 staining) Western blot analysis (poly-ADP ribose polymerase [PARP] cleavage), and caspase3/7 activity. Results demonstrated a significant increase in the apoptotic fraction (JC-1 staining) following combination treatment, when compared to individual effect. This was accompanied by the activation of caspases (caspase 3/7) and the PARP cleavage. Western blot results also revealed that combination treatment of TA with curcumin or EF31 significantly decreased expression of Sp1, Nuclear Factor-kappa light chain enhancer of B cells (NF-kB), and survivin, and modulated the expression of proteins associated with the cell cycle. These pre-clinical results demonstrate that the anti-cancer small molecule, Tolfenamic Acid, may enhance the therapeutic efficacy of curcumin or curcumin analogs in colon cancer. Mechanistic studies to delineate the pathways involved in combination treatment are under investigation. Citation Format: Umesh T. Sankpal, Ganji Purnachandra Nagaraju, Myrna Hurtado, Sriharika R. Gottipolu, Bassel El-Rayes, Mamoru Shoji, Christopher G. Jordan, Riyaz Basha. Combination of anti-cancer small molecule Tolfenamic Acid and curcumin effectively inhibits colon cancer cell growth. [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 2544. doi:10.1158/1538-7445.AM2015-2544
-
Tolfenamic Acid reduces tau and cdk5 levels implications for dementia and tauopathies
Journal of Neurochemistry, 2015Co-Authors: Lina Adwan, Gehad M Subaiea, Riyaz Basha, Nasser H ZawiaAbstract:Tau and its aggregates are linked to the pathology of Alzheimer’s disease (AD) and other tauopathies and, therefore, are explored as therapeutic targets for such disorders. Tau belongs to a family of microtubule-associated proteins (MAPs) that promote microtubule assembly. When hyperphosphorylated, tau becomes prone to forming aggregates. Increased brain levels of hyperphosphorylated tau correlate with dementia. Specificity protein 1 (Sp1), a transcription factor elevated in AD, is responsible for the transcription of AD-related proteins including the amyloid precursor protein (APP), tau, and its cyclin dependent kinase-5 (CDK5) activators. Tolfenamic Acid promotes the degradation of Sp1, our previous studies demonstrated its ability to downregulate transcriptional targets of Sp1 like APP and reduce amyloid beta (Aβ), the main component of AD plaques. In this study, we administered Tolfenamic Acid daily to hemizygous R1.40 transgenic mice for 34 days, and examined tau and CDK5 gene and protein expression within the brain. Our results demonstrate that Tolfenamic Acid lowers tau mRNA and protein, as well as the levels of its phosphorylated form and CDK5. Thus, we present a drug candidate that inhibits the transcription of multiple major intermediates in AD pathology, thereby helping uncover a new mechanism-based approach for targeting AD.
-
Anti-leukemic response of a NSAID, Tolfenamic Acid
Targeted Oncology, 2014Co-Authors: Robert M Sutphin, Umesh T Sankpal, Sarah F Connelly, Chris M Lee, Don Eslin, Moeez Khan, Hima Pius, Riyaz BashaAbstract:Tolfenamic Acid (TA), a non-steroidal anti-inflammatory drug, is known to inhibit human cancer cells and mouse tumor growth in some cancer models; however, its anti-leukemic response has not been evaluated. TA targets specificity protein (Sp) transcription factors that mediate the expression of several genes associated with cancer including survivin, a key member of inhibitor of apoptosis protein family. Our aim was to test the anti-leukemic efficacy of TA in pre-clinical experiments. The anti-leukemic response of TA was determined using Jurkat and Nalm-6 cell lines. Cells were treated with increasing (25/50/75 μM) concentrations of TA, and cell viability was measured at 24, 48, and 72 h post-treatment. TA showed a steady and consistent decrease in cell viability following a clear dose and time dependent response. Apoptosis and cell cycle analysis was performed using flow cytometry. Results showed a significant increase in the apoptotic fraction (annexin V positive) following TA treatment, while cell cycle phase distribution analysis showed G_0/G_1 arrest. TA-induced apoptosis was further confirmed by examining the activation of caspase 3/7 and the expression of cleaved PARP. TA modulated the expression of critical candidates associated with the early phases of cell cycle and validated its efficacy in causing G_0/G_1 arrest. The Western blot results revealed that TA significantly decreases Sp1 and survivin expression. These results demonstrate that the anti-leukemic response of TA occurs potentially through targeting Sp1 and inhibiting survivin and suggest the efficacy of TA as a novel therapeutic agent for leukemia.
Stephen Safe - One of the best experts on this subject based on the ideXlab platform.
-
Safe S: Tolfenamic Acid inhibits esophageal cancer through repression of specificity proteins and c-met. Carcinogenesis
2016Co-Authors: Sabitha Papineni, Stephen Safe, Ala Abudayyeh, Maen Abdelrahim, Syng Ook Lee, Sudhakar Chintharlapalli, Robert Burghardt, Cheryl Baker, Luis Herrera, Division Of NephrologyAbstract:* Authors contributed equally. Running Title: Tolfenamic Acid block esophageal cancer growt
-
effect of Tolfenamic Acid on canine cancer cell proliferation specificity protein sp transcription factors and sp regulated proteins in canine osteosarcoma mammary carcinoma and melanoma cells
Journal of Veterinary Internal Medicine, 2012Co-Authors: Heather L Wilson, Stephen Safe, Gayathri Chadalapaka, Indira Jutooru, Sabina Sheppard, Catherine PfentAbstract:Background Tolfenamic Acid (TA) is an NSAID currently under investigation as an anticancer agent in humans. TA induces proteosome-dependent degradation of transcription factors Sp 1, 3, and 4. These proteins are known to be overexpressed in many human cancers. Hypothesis To evaluate the protein expression of Sps in canine tissue, and efficacy of TA against several canine tumor cell lines. Methods Six canine cell lines (2 osteosarcoma, 2 mammary carcinoma, 2 melanoma) were evaluated. Protein levels of Sp 1–4 and their downstream targets were evaluated using Western Blots. Cell survival and TUNEL assays were performed on cell lines, and Sp1 expression was evaluated on histologic samples from archived canine cases. Animals Six immortalized canine cancer cell lines derived from dogs were used. Archived tissue samples were also used. Results Sps were highly expressed in all 6 cell lines and variably expressed in histologic tissues. TA decreased expression of Sps 1–4 in all cell lines. All of the downstream targets of Sps were inhibited in the cell lines. Variable Sp1 expression was identified in all histologic samples examined. TA significantly inhibited cell survival in all cell lines in a dose dependant fashion. The number of cells undergoing apoptosis was significantly increased (P < .05) in all cell lines after exposure to TA in a dose-dependent fashion. Conclusions, and Clinical Importance Tolfenamic Acid is a potential anticancer NSAID and further investigation is needed to determine its usefulness in a clinical setting.
-
Chemopreventive effects of Tolfenamic Acid against esophageal tumorigenesis in rats
Investigational New Drugs, 2012Co-Authors: Pius Maliakal, Stephen Safe, Cheryl H Baker, Ala Abudayyeh, Maen Abdelrahim, Umesh T Sankpal, Cima Maliakal, Luis J. Herrera, Sumanth Kaja, Riyaz BashaAbstract:The primary objective of this study is to identify small molecules that target critical transcription factors for potential application in the chemoprevention of esophageal cancer. Specificity proteins (Sp) play a critical role in the growth and metastasis of several malignancies including esophageal cancer. Researchers at the M. D. Anderson Cancer Center Orlando Cancer Research Institute have reported previously that Tolfenamic Acid (TA) inhibits cancer cell proliferation and tumor growth through the degradation of Sp1, Sp3, and Sp4. We evaluated the chemopreventive properties of TA against esophageal tumorigenesis in N -nitrosomethylbenzylamine (NMBA)-induced murine tumor model. Fischer-344 rats were treated with NMBA (0.5 mg/kg s.c. 3 times a week) for 5 weeks to initiate the tumor formation, and then treated with 50 mg/kg TA from week 6 through week 25. Tumor incidence, tumor multiplicity (number of papilloma per rat), and tumor volume were evaluated after 25 weeks. All rats in the control group that received only NMBA developed lesions (100% incidence), while the TA-treated group showed significantly lower (33%) tumor incidence and tumor multiplicity. Furthermore, the tumor volume was significantly diminished in the TA-treated group when compared with the control group. Using small molecules such as TA to target key transcription factors associated with tumorigenesis for the prevention of esophageal malignancies is a new and promising strategy. Results of the current study provide evidence that TA, when given orally after tumor initiation, can significantly suppress tumorigenesis induced by carcinogenic nitrosamines in rats. These appealing results demonstrate that TA may potentially serve as an effective chemopreventive agent in patient populations vulnerable to esophageal cancer.
-
therapeutic applications of nsaids in cancer special emphasis on Tolfenamic Acid
Frontiers in Bioscience, 2011Co-Authors: Riyaz Basha, Stephen Safe, James L Abbruzzese, C T Baker, Umesh T Sankpal, Sarfraz Ahmad, Maen AbdelrahimAbstract:Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts long-term; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of Tolfenamic Acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on Tolfenamic Acid.
-
Tolfenamic Acid inhibits esophageal cancer through repression of specificity proteins and c met
Carcinogenesis, 2009Co-Authors: Sabitha Papineni, Cheryl H Baker, Ala Abudayyeh, Maen Abdelrahim, Syng Ook Lee, Sudhakar Chintharlapalli, Luis J. Herrera, Robert C Burghardt, Stephen SafeAbstract:The non-steroidal anti-inflammatory drug Tolfenamic Acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.
Umesh T Sankpal - One of the best experts on this subject based on the ideXlab platform.
-
copper Tolfenamic Acid evaluation of stability and anti cancer activity
Investigational New Drugs, 2019Co-Authors: Myrna Hurtado, Umesh T Sankpal, Jaya Chhabra, Deondra T Brown, Rajasekhar Maram, Rafid Patel, Raj K Gurung, Jerry W Simecka, Alvin A Holder, Riyaz BashaAbstract:The non-steroidal anti-inflammatory drug, Tolfenamic Acid (TA) acts as an anti-cancer agent in several adult and pediatric cancer models. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, [Cu(TA)2(bpy)] (Cu-TA) has been synthesized in order to enhance therapeutic activity. In this study, we synthesized Cu-TA using an established method, characterized it by UV visible spectroscopy and Fourier-transform infrared spectroscopy (FTIR), and tested its anti-cancer activity using twelve cell lines representing various cancers, such as Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, pancreatic and prostate. The anti-proliferative activity of Cu-TA was determined at 48 h post-treatment and compared with the parental compound, TA. The IC50 values were calculated using GraphPad Prism software. The biological stability of Cu-TA was evaluated using twelve-month-old powder and six-month-old stock solution. Cardiomyocytes (H9C2) were used to test the cytotoxicity in non-malignant cells. Cu-TA showed higher anti-proliferative activity, and the IC50 values were 30 to 80% lower when compared with TA. H9C2 cells were non-responsive to Cu-TA, suggesting that it is selective towards malignant cells. Comparison of the twelve-month-old powder and six-month-old stock solution using the Panc1 cell line showed similar IC50 values (<5% variation), confirming the stability of Cu-TA either in powder or solution form. These findings demonstrate the potential of Cu-TA as an effective anti-cancer agent. Further studies to delineate the detailed mechanism of action of Cu-TA for specific cancer model are underway.
-
Tolfenamic Acid induced alterations in genes and pathways in pancreatic cancer cells
Oncotarget, 2017Co-Authors: Umesh T Sankpal, Steve Goodison, Michelle Jonespauley, Myrna Hurtado, Fan Zhang, Riyaz BashaAbstract:// Umesh T. Sankpal 1 , Steve Goodison 2 , Michelle Jones-Pauley 1 , Myrna Hurtado 3 , Fan Zhang 3 , Riyaz Basha 1, 3 1 Texas College of Osteopathic Medicine, University of North Texas Health Science Center, TX, USA 2 Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA 3 Institute for Molecular Medicine, University of North Texas Health Science Center, TX, USA Correspondence to: Riyaz Basha, email: riyaz.basha@unthsc.edu Keywords: Tolfenamic Acid, pancreatic cancer, Sp1, microarray analysis Received: November 04, 2016 Accepted: January 05, 2017 Published: January 14, 2017 ABSTRACT Non-steroidal anti-inflammatory drugs (NSAIDs) are being tested extensively for their role in the treatment and prevention of several cancers. Typically NSAIDs exhibit anti-tumor activities via modulation of cyclooxygenase (COX)-dependent mechanisms, however, an anti-cancer NSAID Tolfenamic Acid (TA) is believed to work through COX-independent pathways. Results from our laboratory and others have demonstrated the anti-cancer activity of TA in various cancer models including pancreatic cancer. TA has been shown to modulate certain cellular processes including, apoptosis, reactive oxygen species and signaling. In this study, molecular profiling was performed to precisely understand the mode of action of TA. Three pancreatic cancer cell lines, L3.6pl, MIA PaCa-2, and Panc1 were treated with TA (50 μM for 48 h) and the changes in gene expression was evaluated using the Affymetrix GeneChip Human Gene ST Array platform. Microarray results were further validated using quantitative PCR for seven genes altered by TA treatment in all three cell lines. Functional analysis of differentially expressed genes (2 fold increase or decrease, p < 0.05) using Ingenuity Pathway Analysis software, revealed that TA treatment predominantly affected the genes involved in cell cycle, cell growth and proliferation, and cell death and survival. Promoter analysis of the differentially expressed genes revealed that they are enriched for Sp1 binding sites, suggesting that Sp1 could be a major contributor in mediating the effect of TA. The gene expression studies identified new targets involved in TA’s mode of action, while supporting the hypothesis about the association of Sp1 in TA mediated effects in pancreatic cancer.
-
abstract 2544 combination of anti cancer small molecule Tolfenamic Acid and curcumin effectively inhibits colon cancer cell growth
Cancer Research, 2015Co-Authors: Umesh T Sankpal, Myrna Hurtado, Ganji Purnachandra Nagaraju, Sriharika R Gottipolu, Bassel F Elrayes, Mamoru Shoji, Christopher G Jordan, Riyaz BashaAbstract:Tolfenamic Acid (TA) is small molecule and non-steroidal anti-inflammatory drug which is known to inhibit human cancer cells and mouse tumor growth in some cancer models. TA is known to target the transcription factor, specificity protein1 (Sp1), that mediates the expression of several genes associated with cancer, including survivin, a key member of the inhibitor of apoptosis proteins (IAP) family. Curcumin is an aromatic constituent of the plant curcuma longa (turmeric) which is extensively studied in some malignancies including breast, pancreatic and colon cancers. Even though curcumin shows a broad spectrum of anti-cancer activity in pre-clinical studies, its clinical application is greatly affected by its low bioavailability. Hence, several strategies to improve the therapeutic response of curcumin are being pursued, including the synthesis of curcumin analogs and using curcumin in combination with other small molecules or drugs to increase bioavailability. In this study, using a colon cancer model, the therapeutic efficacy of curcumin and a curcumin analog EF31 in combination with an anti-cancer small molecule TA was evaluated. Colon cancer cell lines HCT116, HT29, and SW620 were treated with TA, curcumin, or EF31 and cell viability was measured at 24, 48, and 72 hours post-treatment. All agents showed a steady and consistent decrease in cell viability, following a clear dose and time-dependent response. Combination of TA with curcumin or EF31 showed higher growth inhibition compared to single agent treatment. Analysis of apoptosis was carried out to determine the mode of growth inhibition, using flow cytometry (JC-1 staining) Western blot analysis (poly-ADP ribose polymerase [PARP] cleavage), and caspase3/7 activity. Results demonstrated a significant increase in the apoptotic fraction (JC-1 staining) following combination treatment, when compared to individual effect. This was accompanied by the activation of caspases (caspase 3/7) and the PARP cleavage. Western blot results also revealed that combination treatment of TA with curcumin or EF31 significantly decreased expression of Sp1, Nuclear Factor-kappa light chain enhancer of B cells (NF-kB), and survivin, and modulated the expression of proteins associated with the cell cycle. These pre-clinical results demonstrate that the anti-cancer small molecule, Tolfenamic Acid, may enhance the therapeutic efficacy of curcumin or curcumin analogs in colon cancer. Mechanistic studies to delineate the pathways involved in combination treatment are under investigation. Citation Format: Umesh T. Sankpal, Ganji Purnachandra Nagaraju, Myrna Hurtado, Sriharika R. Gottipolu, Bassel El-Rayes, Mamoru Shoji, Christopher G. Jordan, Riyaz Basha. Combination of anti-cancer small molecule Tolfenamic Acid and curcumin effectively inhibits colon cancer cell growth. [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 2544. doi:10.1158/1538-7445.AM2015-2544
-
Anti-leukemic response of a NSAID, Tolfenamic Acid
Targeted Oncology, 2014Co-Authors: Robert M Sutphin, Umesh T Sankpal, Sarah F Connelly, Chris M Lee, Don Eslin, Moeez Khan, Hima Pius, Riyaz BashaAbstract:Tolfenamic Acid (TA), a non-steroidal anti-inflammatory drug, is known to inhibit human cancer cells and mouse tumor growth in some cancer models; however, its anti-leukemic response has not been evaluated. TA targets specificity protein (Sp) transcription factors that mediate the expression of several genes associated with cancer including survivin, a key member of inhibitor of apoptosis protein family. Our aim was to test the anti-leukemic efficacy of TA in pre-clinical experiments. The anti-leukemic response of TA was determined using Jurkat and Nalm-6 cell lines. Cells were treated with increasing (25/50/75 μM) concentrations of TA, and cell viability was measured at 24, 48, and 72 h post-treatment. TA showed a steady and consistent decrease in cell viability following a clear dose and time dependent response. Apoptosis and cell cycle analysis was performed using flow cytometry. Results showed a significant increase in the apoptotic fraction (annexin V positive) following TA treatment, while cell cycle phase distribution analysis showed G_0/G_1 arrest. TA-induced apoptosis was further confirmed by examining the activation of caspase 3/7 and the expression of cleaved PARP. TA modulated the expression of critical candidates associated with the early phases of cell cycle and validated its efficacy in causing G_0/G_1 arrest. The Western blot results revealed that TA significantly decreases Sp1 and survivin expression. These results demonstrate that the anti-leukemic response of TA occurs potentially through targeting Sp1 and inhibiting survivin and suggest the efficacy of TA as a novel therapeutic agent for leukemia.
-
anticancer activity of Tolfenamic Acid in medulloblastoma a preclinical study
Tumor Biology, 2013Co-Authors: Umesh T Sankpal, Robert M Sutphin, Chris M Lee, Don Eslin, Pius Maliakal, Liz Abraham, Riyaz BashaAbstract:Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that Tolfenamic Acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5–50 μg/ml), and cell viability was measured at 1–3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 μg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ~40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin.
Seongho Lee - One of the best experts on this subject based on the ideXlab platform.
-
chemopreventive properties of Tolfenamic Acid a mechanistic review
Current Medicinal Chemistry, 2018Co-Authors: David Feldman, Elizabeth Leahy, Seongho LeeAbstract:Tolfenamic Acid is one of the conventional non-steroidal anti-inflammatory drugs (NSAIDs) commonly used for the treatment of inflammation, migraines and pain. There has been a growing body of experimental evidence that Tolfenamic Acid possesses anti-cancer activity. However, in order to develop a therapeutic strategy using Tolfenamic Acid for the treatment of cancer, further research is required to highlight reliable cellular and molecular mechanisms of anti-cancer properties. Tolfenamic Acid has been shown to alter the expression of several genes that represent cancer hallmarks including apoptosis, growth arrest, angiogenesis and metastasis. Recently, a couple of research groups including ours reported that Tolfenamic Acid targets multiple oncogenic or tumor suppressive signaling pathways in various types of cancer models. Here, we highlight multiple molecular targets responsible for the anti-cancer mechanism of Tolfenamic Acid and the benefits of combinational use of this drug with other anti-cancer drugs.
-
Tolfenamic Acid downregulates β catenin in colon cancer
International Immunopharmacology, 2016Co-Authors: Zhiyuan Lou, Seung Joon Baek, Seongho LeeAbstract:Tolfenamic Acid is one of the fenamic Acid-derived non-steroid anti-inflammatory drugs (NSAIDs) and has been shown to exhibit anti-cancer activities in several types of cancer. Both mutations and aberrant expression of β-catenin are highly associated with progression of cancer. Therefore, β-catenin is considered to be a promising molecular target for cancer prevention and treatment. The current study investigates the role of Tolfenamic Acid on β-catenin expression in colon cancer. Treatment with Tolfenamic Acid led to inhibition of cell growth and down-regulation of β-catenin expression in a dose- and time-dependent manner in human colon cancer cell lines. Reduction of β-catenin upon Tolfenamic Acid treatment was associated with ubiquitin-mediated proteasomal degradation, without affecting mRNA level and promoter activity of β-catenin. In addition, treatment with Tolfenamic Acid downregulated Smad2 and Smad3 expression, while overexpression of Smad2, but not Smad3, blocked Tolfenamic Acid-induced suppression of β-catenin expression. Tolfenamic Acid also decreased expression of β-catenin target genes, including vascular endothelial growth factor (VEGF). Compared to adjacent normal tissue, intestinal tumor tissues of Apc(Min/+) mice exhibited increased expression of β-catenin, Smad2, Smad3, and VEGF, which were down-regulated with Tolfenamic Acid treatment at a dose of 50mg/kg body weight. In conclusion, our findings suggest that Tolfenamic Acid inhibits growth of colon cancer cells through downregulation of Smad2 and, subsequently, facilitating ubiquitin-proteasome-mediated β-catenin degradation in colon cancer.
-
Tolfenamic Acid suppresses inflammatory stimuli mediated activation of nf κb signaling
Biomolecules & Therapeutics, 2015Co-Authors: Hong Jun Shao, Zhiyuan Lou, Jin Boo Jeong, Kui Jin Kim, Jihye Lee, Seongho LeeAbstract:Tolfenamic Acid (TA) is a traditional non-steroid anti-inflammatory drug (NSAID) and has been broadly used for the treatment of migraines. Nuclear factor kappa B (NF-κB) is a sequence-specific transcription factor and plays a key role in the development and progression of inflammation and cancer. We performed the current study to investigate the underlying mechanisms by which TA suppresses inflammation focusing on NF-κB pathway in TNF-α stimulated human normal and cancer cell lines and lipopolysaccharide (LPS)-stimulated mouse macrophages. Different types of human cells (HCT116, HT-29 and HEK293) and mouse macrophages (RAW264.7) were pre-treated with different concentrations of TA and then exposed to inflammatory stimuli such as TNF-α and LPS. Transcriptional activity of NF-κB, IκB-α-degradation, p65 translocation and mitogen-activated protein kinase (MAPK) activations were measured using luciferase assay and Western blots. Pre-treatment of TA repressed TNF-α- or LPS-stimulated NF-κB transactivation in a dose-dependent manner. TA treatment reduced degradation of IκB-α and subsequent translocation of p65 into nucleus. TA significantly down-regulated the phosphorylation of c-Jun N-terminal kinase (JNK). However, TA had no effect on NF-κB signaling and JNK phosphorylation in HT-29 human colorectal cancer cells. TA possesses anti-inflammatory activities through suppression of JNK/NF-κB pathway in different types of cells.
-
the involvement of endoplasmic reticulum stress in the suppression of colorectal tumorigenesis by Tolfenamic Acid
Cancer Prevention Research, 2013Co-Authors: Xiaobo Zhang, Seongho Lee, Jin Boo Jeong, Kyungwon Min, Michael F Mcentee, Seung Joon BaekAbstract:The nonsteroidal anti-inflammatory drug Tolfenamic Acid (TA) has been shown to suppress cancer cell growth and tumorigenesis in different cancer models. However, the underlying mechanism by which TA exerts its anti-tumorigenic effect remains unclear. Previous data from our group and others indicate that TA alters expression of apoptosis- and cell cycle arrest-related genes in colorectal cancer cells. Here, we show that TA markedly reduced the number of polyps and tumor load in APCmin/+ mice, accompanied with cyclin D1 down-regulation in vitro and in vivo. Mechanistically, TA promotes endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) signaling pathway, of which PERK-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) induces the repression of cyclin D1 translation. Moreover, the PERK-eIF2α-ATF4 branch of the UPR pathway plays a role in TA-induced apoptosis in colorectal cancer cells, as silencing ATF4 attenuates TA-induced apoptosis. Taken together, these results suggest ER stress is involved in TA-induced inhibition of colorectal cancer cell growth, which could contribute to anti-tumorigenesis in a mouse model.
-
reactive oxygen species mediate Tolfenamic Acid induced apoptosis in human colorectal cancer cells
Archives of Biochemistry and Biophysics, 2013Co-Authors: Jin Boo Jeong, Seung Joon Baek, Jieun Choi, Seongho LeeAbstract:Several studies have shown substantial evidences that non-steroidal anti-inflammatory drugs (NSAIDs) exert anticancer effects by generating reactive oxygen species (ROS). Tolfenamic Acid (TA) is one of the traditional NSAIDs widely used for treatment of migraine. TA has anti-cancer activities in several human cancer models. In this study, we report that generation of ROS by TA leads to apoptosis through modulation of several pathways in human colorectal cancer cells. TA induced rapid generation of intracellular ROS and led to an increase of phosphorylation of H2AX, a tail moment of comet and distribution of fragmented genomic DNA traces. Treatment of N-acetyl-l-cysteine (NAC) abolished TA-induced phosphorylation of H2AX and apoptosis. Treatment of TA resulted in an increase of nuclear factor-kappaB (NF-κB) transcriptional activity through inhibitor of kappa B (IκB-α) degradation and subsequent p65 nuclear translocation. In addition, TA increased apoptosis-inducing activating transcription factor 3 (ATF3) expression. However, the treatment of NAC abolished TA-mediated NF-κB activation and ATF3 expression and chemical inhibition of NF-κB or knockdown of p65 significantly attenuated TA-induced ATF3 expression. Our finding indicates that ROS-mediated DNA damage and subsequent activation of NF-κB and ATF3 expression plays a significant role in TA-induced apoptosis in human colorectal cancer cells.
Maen Abdelrahim - One of the best experts on this subject based on the ideXlab platform.
-
Safe S: Tolfenamic Acid inhibits esophageal cancer through repression of specificity proteins and c-met. Carcinogenesis
2016Co-Authors: Sabitha Papineni, Stephen Safe, Ala Abudayyeh, Maen Abdelrahim, Syng Ook Lee, Sudhakar Chintharlapalli, Robert Burghardt, Cheryl Baker, Luis Herrera, Division Of NephrologyAbstract:* Authors contributed equally. Running Title: Tolfenamic Acid block esophageal cancer growt
-
Chemopreventive effects of Tolfenamic Acid against esophageal tumorigenesis in rats
Investigational New Drugs, 2012Co-Authors: Pius Maliakal, Stephen Safe, Cheryl H Baker, Ala Abudayyeh, Maen Abdelrahim, Umesh T Sankpal, Cima Maliakal, Luis J. Herrera, Sumanth Kaja, Riyaz BashaAbstract:The primary objective of this study is to identify small molecules that target critical transcription factors for potential application in the chemoprevention of esophageal cancer. Specificity proteins (Sp) play a critical role in the growth and metastasis of several malignancies including esophageal cancer. Researchers at the M. D. Anderson Cancer Center Orlando Cancer Research Institute have reported previously that Tolfenamic Acid (TA) inhibits cancer cell proliferation and tumor growth through the degradation of Sp1, Sp3, and Sp4. We evaluated the chemopreventive properties of TA against esophageal tumorigenesis in N -nitrosomethylbenzylamine (NMBA)-induced murine tumor model. Fischer-344 rats were treated with NMBA (0.5 mg/kg s.c. 3 times a week) for 5 weeks to initiate the tumor formation, and then treated with 50 mg/kg TA from week 6 through week 25. Tumor incidence, tumor multiplicity (number of papilloma per rat), and tumor volume were evaluated after 25 weeks. All rats in the control group that received only NMBA developed lesions (100% incidence), while the TA-treated group showed significantly lower (33%) tumor incidence and tumor multiplicity. Furthermore, the tumor volume was significantly diminished in the TA-treated group when compared with the control group. Using small molecules such as TA to target key transcription factors associated with tumorigenesis for the prevention of esophageal malignancies is a new and promising strategy. Results of the current study provide evidence that TA, when given orally after tumor initiation, can significantly suppress tumorigenesis induced by carcinogenic nitrosamines in rats. These appealing results demonstrate that TA may potentially serve as an effective chemopreventive agent in patient populations vulnerable to esophageal cancer.
-
Tolfenamic Acid interrupts the de novo synthesis of the β amyloid precursor protein and lowers amyloid beta via a transcriptional pathway
Current Alzheimer Research, 2011Co-Authors: Lina Adwan, Gehad M Subaiea, Maen Abdelrahim, Riyaz Basha, Nasser H ZawiaAbstract:Amyloid beta (Aβ) peptides are related to the pathogenesis of Alzheimers disease (AD). The search for therapeutic strategies that lower these peptides has mainly focused on the proteolytic processing of the β-amyloid precursor protein (APP), and other post-transcriptional pathways. The transcription factor specificity protein 1 (Sp1) is vital for the regulation of several genes involved in AD including APP and the beta site APP cleaving enzyme 1 (BACE1). We have previously reported that Tolfenamic Acid promotes the degradation of Sp1 protein (SP1) in pancreatic human cancer cells and mice tumors. This study examines the ability of Tolfenamic Acid to reduce SP1 levels, and thereby decrease APP transcription and Aβ levels in rodent brains. Tolfenamic Acid was administered by oral gavage to C57BL/6 mice at variable dosages and for different time periods. Results have shown that Tolfenamic Acid was able to downregulate brain protein levels of SP1, APP, and Aβ. These findings demonstrate that interference with upstream transcriptional pathways can lower pathogenic intermediates associated with AD, and thus Tolfenamic Acid represents a novel approach for the development of a therapeutic intervention for AD.
-
therapeutic applications of nsaids in cancer special emphasis on Tolfenamic Acid
Frontiers in Bioscience, 2011Co-Authors: Riyaz Basha, Stephen Safe, James L Abbruzzese, C T Baker, Umesh T Sankpal, Sarfraz Ahmad, Maen AbdelrahimAbstract:Non-steroidal anti-inflammatory drugs (NSAIDs) are primarily used for the treatment of acute or chronic conditions with pain and inflammation. Evidence from a wide range of sources suggested that chronic administration of NSAIDs reduced the risk of cancer incidences. Both the epidemiological and animal studies showed an inverse association between the incidence of various cancers and the use of aspirin or other NSAIDs. The chemopreventive and therapeutic interventions of NSAIDs in cancer are obvious; however, the instigation of drug and treatment period depends on the study objective. Typically, prevention involves initiating the medication before the appearance of clinical symptoms and lasts long-term; while treatment could be short-term and contingent to the response of patient to the medication. Recent studies from our laboratories provided substantial evidence on the anti-cancer activity of Tolfenamic Acid, a NSAID for the potential applications in pancreatic, esophageal and lung cancers. In this review, we provide a summary on the potential benefits of NSAIDs in a variety of human cancers with more emphasis on Tolfenamic Acid.
-
Tolfenamic Acid inhibits esophageal cancer through repression of specificity proteins and c met
Carcinogenesis, 2009Co-Authors: Sabitha Papineni, Cheryl H Baker, Ala Abudayyeh, Maen Abdelrahim, Syng Ook Lee, Sudhakar Chintharlapalli, Luis J. Herrera, Robert C Burghardt, Stephen SafeAbstract:The non-steroidal anti-inflammatory drug Tolfenamic Acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.