Cyclooxygenase-2 (COX-2) is induced in response to proinflammatory conditions, and it is not only a key enzyme in the inflammatory process, but also seems to be highly expressed in various types of cancer cells. On the other hand, it is well documented that chemical compounds with spiro scaffolds in their structure could be effective chemical agents against cancer types. In this study, the cytotoxicity effects of spiroisoxazoline derivatives containing naphthalinone and chromanone spiro-bridge were investigated. The cytotoxicity effects of compounds 7a-7h were evaluated by performing the MTT assay on the HT-29 (colorectal cancer), MCF-7 (breast cancer), and HEK-293 (normal kidney) cell lines. After that, a compound with high yield and remarkable cytotoxic activity was selected to analyze the cell cycle and apoptosis mechanism. The most effective cytotoxic activity was observed on HT-29 and MCF-7 cell lines of compounds 7b (IC50 value: 1.07±0.28 µM) and 7f (IC50 value: 11.92±1.07 µM). None of the compounds had a toxic effect on normal HEK-293 cells, except for compound 7g with an IC50 value of 21.30±16.14 µM, whose effect was much lower than that of cisplatin and doxorubicin, known as anti-cancer agents. Subsequently, compound 7e with significant yield and cytotoxic activity was investigated to evaluate cell cycle and apoptosis. The result showed that compound 7e induced significant G0/G1 cell cycle arrest and apoptosis in HT-29 cells The selective COX-2 inhibitor compounds with spiroisoxazoline core structure could be suitable scaffolds for cytotoxic effects.
{"title":"Anti-Cancer Activity Evaluation of Naphthalenonic and Chromanonic\u0000Spiroisoxazoline Derivatives as Selective COX-2 Inhibitors on HT29 Cell\u0000Lines","authors":"Hourieh Kalhor, Tahereh Komeili Movahhed, S. Mousavi, Masoumeh Sadri Qomi, A. Abolhasani, Masoumeh Mirani, Minoo Hosseini Rad, Fatemeh Heidari, Hoda Hosseini","doi":"10.2174/012212697x274833240408033609","DOIUrl":"https://doi.org/10.2174/012212697x274833240408033609","url":null,"abstract":"\u0000\u0000Cyclooxygenase-2 (COX-2) is induced in response to proinflammatory\u0000conditions, and it is not only a key enzyme in the inflammatory process, but also seems to be\u0000highly expressed in various types of cancer cells. On the other hand, it is well documented that\u0000chemical compounds with spiro scaffolds in their structure could be effective chemical agents\u0000against cancer types.\u0000\u0000\u0000\u0000In this study, the cytotoxicity effects of spiroisoxazoline derivatives containing naphthalinone and chromanone spiro-bridge were investigated.\u0000\u0000\u0000\u0000The cytotoxicity effects of compounds 7a-7h were evaluated by performing the MTT\u0000assay on the HT-29 (colorectal cancer), MCF-7 (breast cancer), and HEK-293 (normal kidney)\u0000cell lines. After that, a compound with high yield and remarkable cytotoxic activity was selected\u0000to analyze the cell cycle and apoptosis mechanism.\u0000\u0000\u0000\u0000The most effective cytotoxic activity was observed on HT-29 and MCF-7 cell lines of\u0000compounds 7b (IC50 value: 1.07±0.28 µM) and 7f (IC50 value: 11.92±1.07 µM). None of the\u0000compounds had a toxic effect on normal HEK-293 cells, except for compound 7g with an IC50\u0000value of 21.30±16.14 µM, whose effect was much lower than that of cisplatin and doxorubicin,\u0000known as anti-cancer agents. Subsequently, compound 7e with significant yield and cytotoxic\u0000activity was investigated to evaluate cell cycle and apoptosis. The result showed that compound\u00007e induced significant G0/G1 cell cycle arrest and apoptosis in HT-29 cells\u0000\u0000\u0000\u0000The selective COX-2 inhibitor compounds with spiroisoxazoline core structure\u0000could be suitable scaffolds for cytotoxic effects.\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":"131 46","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141656302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.2174/012212697x308365240529100442
P. Maurya, Ashutosh Mani
Colorectal cancer (CRC) is the third most commonly occurring cancer and the second leading cause of cancer-related deaths worldwide. Conventional treatments for CRC, such as surgery, chemotherapy, and radiotherapy, have long been the primary options for patients. However, their therapeutic success rates are relatively low, necessitating the development of novel technologies. The prognosis for metastatic CRC patients has historically been unsatisfactory. Recent efforts have focused on advancing our understanding of CRC progression, leading to improvements in CRC management and the identification of key regulatory genes involved in colorectal cancer. The complex interaction between the tumor microenvironment and CRC progression has unveiled new immunotherapy targets, including immune checkpoint inhibitors and CAR T-cell-based therapies. Additionally, novel approaches targeting cell signaling pathways that promote cell proliferation and metastasis in CRC show great potential for improving patient outcomes. This article explores and summarizes the epidemiology, carcinogenesis, and stages of CRC, as well as current treatment strategies and drug targets. It highlights the molecular mechanisms underlying tumorigenesis and progression in colorectal cancer.
{"title":"Current Perspective and Treatment Strategies in Targeted Therapy for\u0000Colorectal Cancer","authors":"P. Maurya, Ashutosh Mani","doi":"10.2174/012212697x308365240529100442","DOIUrl":"https://doi.org/10.2174/012212697x308365240529100442","url":null,"abstract":"\u0000\u0000Colorectal cancer (CRC) is the third most commonly occurring cancer and the second\u0000leading cause of cancer-related deaths worldwide. Conventional treatments for CRC, such as\u0000surgery, chemotherapy, and radiotherapy, have long been the primary options for patients. However, their therapeutic success rates are relatively low, necessitating the development of novel\u0000technologies. The prognosis for metastatic CRC patients has historically been unsatisfactory.\u0000Recent efforts have focused on advancing our understanding of CRC progression, leading to improvements in CRC management and the identification of key regulatory genes involved in colorectal cancer. The complex interaction between the tumor microenvironment and CRC progression has unveiled new immunotherapy targets, including immune checkpoint inhibitors and CAR\u0000T-cell-based therapies. Additionally, novel approaches targeting cell signaling pathways that\u0000promote cell proliferation and metastasis in CRC show great potential for improving patient outcomes. This article explores and summarizes the epidemiology, carcinogenesis, and stages of\u0000CRC, as well as current treatment strategies and drug targets. It highlights the molecular mechanisms underlying tumorigenesis and progression in colorectal cancer.\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":"97 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141657392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-29DOI: 10.2174/2212697x09666220629161535
André Nunes Volpini, Igor José de Souza Marques, I. D. Cavalcanti
The main toxicity of cisplatin is nephrotoxicity, but more and more studies have highlighted and unveiled the mechanisms of cisplatin toxicity, and the neurotoxicity has been standing out. We aimed to bring together the main studies that highlight the neurotoxicity of cisplatin in the treatment of cancer patients. We performed a literature review using the keywords “Neurotoxicity”, “Cisplatin”, “Oncology Therapy”, and “Chemotherapy” in the SciELO, PubMed, Sciencedirect, MEDLINE, Scifinder, and CAplus databases. We selected 60 articles published between 1983 and 2021 that report the mechanisms of cisplatin toxicity or which provide clinical data on the neurotoxicity profile of cisplatin as monotherapy and as a combination therapy, highlighting that one of the main neurotoxicity of cisplatin is in the development of peripheral neuropathy. Cisplatin is neurotoxic and can induce the development of peripheral neuropathy and the combination with neurotoxic drugs such as paclitaxel and vincristine only contributes to the increase in neurological toxicity. Thus, we emphasize the importance of evaluating the neurotoxicity of cisplatin, especially in patients who use protocols that contain other antineoplastic agents that are also neurotoxic.
{"title":"Neurotoxicity of Cisplatin as Monotherapy or Combined Chemotherapy in Cancer Treatment","authors":"André Nunes Volpini, Igor José de Souza Marques, I. D. Cavalcanti","doi":"10.2174/2212697x09666220629161535","DOIUrl":"https://doi.org/10.2174/2212697x09666220629161535","url":null,"abstract":"\u0000\u0000The main toxicity of cisplatin is nephrotoxicity, but more and more studies\u0000have highlighted and unveiled the mechanisms of cisplatin toxicity, and the neurotoxicity has been\u0000standing out.\u0000\u0000\u0000\u0000We aimed to bring together the main studies that highlight the neurotoxicity of cisplatin in\u0000the treatment of cancer patients.\u0000\u0000\u0000\u0000We performed a literature review using the keywords “Neurotoxicity”, “Cisplatin”, “Oncology Therapy”, and “Chemotherapy” in the SciELO, PubMed, Sciencedirect, MEDLINE, Scifinder,\u0000and CAplus databases.\u0000\u0000\u0000\u0000We selected 60 articles published between 1983 and 2021 that report the mechanisms of cisplatin toxicity or which provide clinical data on the neurotoxicity profile of cisplatin as monotherapy\u0000and as a combination therapy, highlighting that one of the main neurotoxicity of cisplatin is in the\u0000development of peripheral neuropathy.\u0000\u0000\u0000\u0000Cisplatin is neurotoxic and can induce the development of peripheral neuropathy and the\u0000combination with neurotoxic drugs such as paclitaxel and vincristine only contributes to the increase\u0000in neurological toxicity. Thus, we emphasize the importance of evaluating the neurotoxicity of cisplatin, especially in patients who use protocols that contain other antineoplastic agents that are also neurotoxic.\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41834934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-10DOI: 10.2174/2212697x08666211210105329
Maria Ayanny de Lima Fernandes, Andreza T. de Aguiar Silva, I. D. Cavalcanti, Adrya Lúcia Peres Bezerra de Medeiros, Lígia Maria de Oliveira Lima, Tâmara Kelly de Castro Gomes
The established dose of chemotherapy is based on the values of the patient's body weight, where variations during treatment can increase the toxicity of chemotherapy, with the development of nephrotoxicity, among other toxicity profiles, as well as in cases of weight gain, patients may receive low doses and compromise the therapeutic response to the tumor. to evaluate weight gain and loss in cancer patients undergoing chemotherapy. Methods: Longitudinal analytical study with patients at the end of chemotherapy treatment of both genders. The type, location of the tumor and the antineoplastic agent used were collected from the medical records, as well as height and weight at the beginning of treatment. At the time of collection, anthropometric assessment was performed using body mass index, arm circumference, arm muscle circumference, triceps skinfold thickness and percentage of weight loss. Among the patients included in the study, 47.5% had a weight gain of around 2.5 kg, while the remaining patients (52.5%) had a weight loss of around 2.8 kg. Of the patients who had GFR, 55.5% had severe PP, 33.4% had no significant loss and 11.1 had significant loss. In the current study, only 22% had a GFR <60ml/min/1.73m², but they would already need to readjust the medication calculation. It is important to evaluate body surface variations and also the GFR to adjust the dose of the antineoplastic agent and to prevent or minimize nephrotoxicity, as well as to reduce the risk of underdosing and inefficiency of the therapy.
{"title":"Weight Gain and Loss In Cancer Patients Undergoing Chemotherapy: Importance of Dose Adjustment","authors":"Maria Ayanny de Lima Fernandes, Andreza T. de Aguiar Silva, I. D. Cavalcanti, Adrya Lúcia Peres Bezerra de Medeiros, Lígia Maria de Oliveira Lima, Tâmara Kelly de Castro Gomes","doi":"10.2174/2212697x08666211210105329","DOIUrl":"https://doi.org/10.2174/2212697x08666211210105329","url":null,"abstract":"\u0000\u0000The established dose of chemotherapy is based on the values of the patient's body weight, where variations during treatment can increase the toxicity of chemotherapy, with the development of nephrotoxicity, among other toxicity profiles, as well as in cases of weight gain, patients may receive low doses and compromise the therapeutic response to the tumor. \u0000\u0000\u0000\u0000\u0000to evaluate weight gain and loss in cancer patients undergoing chemotherapy. Methods: Longitudinal analytical study with patients at the end of chemotherapy treatment of both genders. The type, location of the tumor and the antineoplastic agent used were collected from the medical records, as well as height and weight at the beginning of treatment. At the time of collection, anthropometric assessment was performed using body mass index, arm circumference, arm muscle circumference, triceps skinfold thickness and percentage of weight loss. \u0000\u0000\u0000\u0000\u0000Among the patients included in the study, 47.5% had a weight gain of around 2.5 kg, while the remaining patients (52.5%) had a weight loss of around 2.8 kg. Of the patients who had GFR, 55.5% had severe PP, 33.4% had no significant loss and 11.1 had significant loss. In the current study, only 22% had a GFR <60ml/min/1.73m², but they would already need to readjust the medication calculation. \u0000\u0000\u0000\u0000\u0000It is important to evaluate body surface variations and also the GFR to adjust the dose of the antineoplastic agent and to prevent or minimize nephrotoxicity, as well as to reduce the risk of underdosing and inefficiency of the therapy.\u0000\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44622793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-10DOI: 10.2174/2212697x08666211210104609
Sumbla Sheikh, A. Sturzu, H. Kalbacher, T. Nägele, U. Ernemann, S. Heckl
In the study of bioactive agents from traditional medicine, mono- and sesquiterpenes represent the main ingredients of essential oils. Till now, only thymoquinone and perillyl alcohol have been clinically tested on glioblastoma. In the present study, we examined the effect of ten different essential oils on three human glioblastoma cell lines and one healthy human cell line. We used confocal laser scanning microscopy, flow cytometry, and cell growth analysis to evaluate cell morphology changes, membrane disruption effects, acute cytotoxicity and effects on the proliferation rate caused by the essential oils pinene, geraniol, eucalyptol, perillaldehyde, limonene, and linalool, perillyl alcohol, myrcene, bisabolol and valencene on human cells. Caspase 3/7 activity was measured to observe apoptosis induced by the essential oils. We found that the cytotoxicity concentrations varied not only between different essential oils but also among different cell lines. Acute cytotoxicity of essential oils was based on cell membrane disruption and that HEK cells were affected to a much higher degree than the Glioblastoma cells. Vacuoles found in surviving glioblastoma cells appeared to be a factor in this effect. Caspase activity did not correlate with the membrane damage observed in the flow cytometry experiments. This is especially evident in the HEK cells that only showed apoptosis with two out of ten essential oils.
{"title":"Differential proliferative and cytotoxic effect of selected components of essential oils on human glioblastoma cells","authors":"Sumbla Sheikh, A. Sturzu, H. Kalbacher, T. Nägele, U. Ernemann, S. Heckl","doi":"10.2174/2212697x08666211210104609","DOIUrl":"https://doi.org/10.2174/2212697x08666211210104609","url":null,"abstract":"\u0000\u0000 In the study of bioactive agents from traditional medicine, mono- and sesquiterpenes represent the main ingredients of essential oils. Till now, only thymoquinone and perillyl alcohol have been clinically tested on glioblastoma. \u0000\u0000\u0000\u0000\u0000In the present study, we examined the effect of ten different essential oils on three human glioblastoma cell lines and one healthy human cell line. \u0000\u0000\u0000\u0000\u0000 We used confocal laser scanning microscopy, flow cytometry, and cell growth analysis to evaluate cell morphology changes, membrane disruption effects, acute cytotoxicity and effects on the proliferation rate caused by the essential oils pinene, geraniol, eucalyptol, perillaldehyde, limonene, and linalool, perillyl alcohol, myrcene, bisabolol and valencene on human cells. Caspase 3/7 activity was measured to observe apoptosis induced by the essential oils. \u0000\u0000\u0000\u0000\u0000We found that the cytotoxicity concentrations varied not only between different essential oils but also among different cell lines. Acute cytotoxicity of essential oils was based on cell membrane disruption and that HEK cells were affected to a much higher degree than the Glioblastoma cells. Vacuoles found in surviving glioblastoma cells appeared to be a factor in this effect. \u0000\u0000\u0000\u0000\u0000Caspase activity did not correlate with the membrane damage observed in the flow cytometry experiments. This is especially evident in the HEK cells that only showed apoptosis with two out of ten essential oils. \u0000\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44262685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-10DOI: 10.2174/2212697x08666211210103711
Deepa R. Bandi, SubbaRao V Tulimilli, Durai Ananda Kumar T., Chandi Kumari Chitturi, A. S. Bettadapura, Suma M. Natraj, S. Madhunapantula
Despite various efforts in preventing and treating SARS-CoV-2 infections; transmission and mortality have been increasing at alarming rates globally. Since its first occurrence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV-2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns. The objective of this study is to identify the ability of HCQ for binding to the most widely studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main protease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ. X-ray crystallographic structures of spike glycoprotein and main protease of SARS-CoV-2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using C-Docker algorithm, and visualized using Discovery studio visualizer. Data from molecular docking studies showed very strong binding of HCQ to the main protease compared to spike glycoprotein. The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.
{"title":"Hydroxychloroquine (HCQ) exhibits better binding to the main protease (Mpro) compared to spike protein (S protein) of SARS-CoV-2: An in-silico analysis","authors":"Deepa R. Bandi, SubbaRao V Tulimilli, Durai Ananda Kumar T., Chandi Kumari Chitturi, A. S. Bettadapura, Suma M. Natraj, S. Madhunapantula","doi":"10.2174/2212697x08666211210103711","DOIUrl":"https://doi.org/10.2174/2212697x08666211210103711","url":null,"abstract":"\u0000\u0000 Despite various efforts in preventing and treating SARS-CoV-2 infections; transmission and mortality have been increasing at alarming rates globally. Since its first occurrence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV-2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns.\u0000\u0000\u0000\u0000\u0000The objective of this study is to identify the ability of HCQ for binding to the most widely studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main protease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ.\u0000\u0000\u0000\u0000\u0000X-ray crystallographic structures of spike glycoprotein and main protease of SARS-CoV-2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using C-Docker algorithm, and visualized using Discovery studio visualizer.\u0000\u0000\u0000\u0000\u0000 Data from molecular docking studies showed very strong binding of HCQ to the main protease compared to spike glycoprotein.\u0000\u0000\u0000\u0000\u0000The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.\u0000\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43518493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-12-06DOI: 10.2174/2212697x08666211206102503
Klara Mladenić, Mirela Sedić
Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool. The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity) leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway. This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for development of chemoresistance and whose targeting might enable design of novel combination strategies to overcome resistance to conventional treatment in CRC.
{"title":"Chemoresistance mechanisms in colon cancer: focus on conventional chemotherapy","authors":"Klara Mladenić, Mirela Sedić","doi":"10.2174/2212697x08666211206102503","DOIUrl":"https://doi.org/10.2174/2212697x08666211206102503","url":null,"abstract":"\u0000\u0000Colorectal cancer (CRC) is a widespread tumour type amongst men and women. Despite the available screening tests, advanced stage CRC is the most frequent diagnosis. It is treated with cytotoxic chemotherapeutics 5-fluorouracil (5-FU), oxaliplatin (Ox) and irinotecan (CPT-11) that eventually lose their effectiveness as chemoresistance develops. \u0000\u0000\u0000\u0000\u0000In this review, the compilation and analysis of PUBMED-retrieved literature data was comprehensively presented and some novel and/or previously poorly described molecular features of CRC unresponsiveness to conventional chemotherapy drugs identified using bioinformatics approach. Complex interactions between previously reported biomarkers of resistance to 5-FU, Ox and CPT-11 were analysed by STRING and cytoHubba accompanied by KEGG pathway enrichment analysis using DAVID functional annotation tool.\u0000\u0000\u0000\u0000\u0000The bioinformatics analysis has revealed that 5-FU affects ribosome biogenesis and functioning (translational activity) leading to colon cancer cells resistance to 5-FU. Unresponsiveness of CRC to Ox was associated with Rap1 signalling pathway, which opens the possibility of using RAP1A inhibitors as an adjuvant to oxaliplatin in CRC. Furthermore, stem cell markers c-Myc and CD44 as well as Akt kinase emerged as novel resistance biomarkers whose pharmacological targeting could elevate the therapeutic efficacy of irinotecan. Lastly, several pathways common to the resistance to all three drugs were revealed including miRNAs in cancer, proteoglycans in cancer, cellular senescence and the sphingolipid signalling pathway.\u0000\u0000\u0000\u0000\u0000This paper gives a comprehensive overview of resistance mechanisms to 5-FU, Ox and irinotecan in colon cancer and reveals several novel molecular players and associated mechanisms that could account for development of chemoresistance and whose targeting might enable design of novel combination strategies to overcome resistance to conventional treatment in CRC.\u0000\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44569207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-30DOI: 10.2174/2212697x08666211130130119
Pir Mohammad Ishfaq, Anjali Mishra, Shivani Mishra, Zaved Ahmad, S. Gayen, Subodh Kumar Jain, S. Tripathi, S. Mishra
Chaga mushroom [Inonotus obliquus] is an edible macrofungus used in traditional and folk medicine for treatment of various gastrointestinal disorders. It has shown potent anti-inflammatory, antioxidant and anticancer effects in several experimental studies including our anti-inflammatory and anticancer effects in colorectal cancer and intestinal inflammation. Whole extract or purified compound ergosterol peroxide from chaga mushroom showed anti-inflammatory mechanism via suppression of NF-κB/iNOS-COX-2 and growth inhibitory mechanism via regulation of apoptosis activation and β-catenin suppression. The emergence of diverse inflammatory and carcinogenic agents like carbon tetrachloride [CCl4] is a potent hepatotoxic chemical that caused liver damage by inducing lipid peroxidation and other oxidative damages. The study was aimed to analyze the biochemical, cellular and molecular mechanism of CCl4 induced chronic liver inflammation and carcinoma and to analyze the effect of the extract of chaga mushroom on liver inflammation and cancer by virtue of anti-inflammatory mechanisms. Physiological, histological and immunohistochemical the physiological functions and cellular functions. Biochemical assays for assessing enzymatic changes in tissues. Molecular simulation and docking studies were performed for proposing the molecular interaction. CCl4-exposed mice exhibited a significant decrease in the body weight followed by altered histopathological signatures in the liver. Supplementation of IOAE showed that treatment restored towards normal structure of the tissues with large round nuclei in most of the cells. CCl4 caused a steep elevation in the levels of SGOT and SGPT to 2.32- and 1.8-fold as compared to control. The LDH level was increased to 447 IU/L in CCl4 treated mice as compared to control [236 IU/L]. Analysis of the oxidant enzyme pathway showed that CCl4 reduced the GSH level to 16.5 μM as compared to control [52 μM], and induced the catalase enzyme activity to 259 U/mL as compared to control [124 U/L]. These physiological and biochemical alterations were restored towards normal levels by IOAE administration. Immunohistochemical staining for caspase-3 and p53 showed that CCl4 notably increased their expressions which were subsequently suppressed by administration of IOAE. The molecular simulation and docking studies using ergosterol peroxide from chaga mushroom with iNOS, COX-2 and TNF-α showed binding energy of -10.5, -8.9 and -9.1 Kcal/mol, respectively. These proteins interacting with ergosterol peroxide suggests an inhibitory effect on these critical proinflammatory signaling proteins. The results point out that IOAE is able to prevent damage of hepatic cells caused by CCl4 in mouse models through anti-inflammatory and growth inhibitory mechanism which can be utilized in natural prevention of the liver toxicity.
{"title":"Inonotus obliquus aqueous extract suppresses carbon tetrachloride induced hepatic injury through modulation of antioxidant enzyme system and anti-inflammatory mechanism","authors":"Pir Mohammad Ishfaq, Anjali Mishra, Shivani Mishra, Zaved Ahmad, S. Gayen, Subodh Kumar Jain, S. Tripathi, S. Mishra","doi":"10.2174/2212697x08666211130130119","DOIUrl":"https://doi.org/10.2174/2212697x08666211130130119","url":null,"abstract":"\u0000\u0000Chaga mushroom [Inonotus obliquus] is an edible macrofungus used in traditional and folk medicine for treatment of various gastrointestinal disorders. It has shown potent anti-inflammatory, antioxidant and anticancer effects in several experimental studies including our anti-inflammatory and anticancer effects in colorectal cancer and intestinal inflammation. Whole extract or purified compound ergosterol peroxide from chaga mushroom showed anti-inflammatory mechanism via suppression of NF-κB/iNOS-COX-2 and growth inhibitory mechanism via regulation of apoptosis activation and β-catenin suppression. The emergence of diverse inflammatory and carcinogenic agents like carbon tetrachloride [CCl4] is a potent hepatotoxic chemical that caused liver damage by inducing lipid peroxidation and other oxidative damages.\u0000\u0000\u0000\u0000\u0000 The study was aimed to analyze the biochemical, cellular and molecular mechanism of CCl4 induced chronic liver inflammation and carcinoma and to analyze the effect of the extract of chaga mushroom on liver inflammation and cancer by virtue of anti-inflammatory mechanisms.\u0000\u0000\u0000\u0000\u0000Physiological, histological and immunohistochemical the physiological functions and cellular functions. Biochemical assays for assessing enzymatic changes in tissues. Molecular simulation and docking studies were performed for proposing the molecular interaction.\u0000\u0000\u0000\u0000\u0000CCl4-exposed mice exhibited a significant decrease in the body weight followed by altered histopathological signatures in the liver. Supplementation of IOAE showed that treatment restored towards normal structure of the tissues with large round nuclei in most of the cells. CCl4 caused a steep elevation in the levels of SGOT and SGPT to 2.32- and 1.8-fold as compared to control. The LDH level was increased to 447 IU/L in CCl4 treated mice as compared to control [236 IU/L]. Analysis of the oxidant enzyme pathway showed that CCl4 reduced the GSH level to 16.5 μM as compared to control [52 μM], and induced the catalase enzyme activity to 259 U/mL as compared to control [124 U/L]. These physiological and biochemical alterations were restored towards normal levels by IOAE administration. Immunohistochemical staining for caspase-3 and p53 showed that CCl4 notably increased their expressions which were subsequently suppressed by administration of IOAE. The molecular simulation and docking studies using ergosterol peroxide from chaga mushroom with iNOS, COX-2 and TNF-α showed binding energy of -10.5, -8.9 and -9.1 Kcal/mol, respectively. These proteins interacting with ergosterol peroxide suggests an inhibitory effect on these critical proinflammatory signaling proteins.\u0000\u0000\u0000\u0000\u0000 The results point out that IOAE is able to prevent damage of hepatic cells caused by CCl4 in mouse models through anti-inflammatory and growth inhibitory mechanism which can be utilized in natural prevention of the liver toxicity.\u0000\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46628015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-11-08DOI: 10.2174/2212697x08666211108095152
C. Wanitpongpun, N. Teawtrakul, T. Lanamtieng, K. Chansung, Chittima Sirijeerachai, Worakamol Amampai, K. Sawanyawisuth
Acute leukemia with febrile neutropenia is at risk for infection. Fungal infection is a serious infection in this setting with a high mortality rate. There is limited data on clinical factors predictive of fungal infection in this setting. This study aimed to evaluate clinical predictive factors of fungal infection in acute leukemia patients with FN. This was a retrospective analytical study and included adult patients diagnosed with acute leukemia, who developed FN, and had positive culture on either bacterial or fungal infection. Predictors for fungal infection were calculated by using logistic regression analysis. A subgroup analysis in patients with acute myeloid leukemia (AML) was also performed. There were 94 patients who met the study criteria. Of those, 29 patients had positive culture for fungus (30.82%): categorized as Aspergillus (19 patients; 65.51%) and Candida (10 patients; 34.49%). The mortality rate was significantly higher in the fungal infection group than the bacterial infection group (24.14% vs 6.15%; p 0.031). There were six factors in the final model predictive of fungal infection with one independent predictor: treatment regimen of Idarubicin plus Ara-C with an adjusted odds ratio of 5.188 (95% CI of 1.386, 19.419). A subgroup analysis for fungal infection in patients with AML showed that only the treatment regimen of Idarubicin plus Ara-C was a significant factor. Its adjusted odds ratio was 5.138 (95% CI of 1.156, 24.467). Treatment with idarubicin and Ara-C may increase the risk of fungal infection in acute leukemia patients with FN.
{"title":"Idarubicin and Ara-C treatment associated with fungal infection in acute leukemia patients with febrile neutropenia","authors":"C. Wanitpongpun, N. Teawtrakul, T. Lanamtieng, K. Chansung, Chittima Sirijeerachai, Worakamol Amampai, K. Sawanyawisuth","doi":"10.2174/2212697x08666211108095152","DOIUrl":"https://doi.org/10.2174/2212697x08666211108095152","url":null,"abstract":"\u0000\u0000 Acute leukemia with febrile neutropenia is at risk for infection. Fungal infection is a serious infection in this setting with a high mortality rate. There is limited data on clinical factors predictive of fungal infection in this setting. \u0000\u0000\u0000\u0000\u0000 This study aimed to evaluate clinical predictive factors of fungal infection in acute leukemia patients with FN.\u0000\u0000\u0000\u0000\u0000 This was a retrospective analytical study and included adult patients diagnosed with acute leukemia, who developed FN, and had positive culture on either bacterial or fungal infection. Predictors for fungal infection were calculated by using logistic regression analysis. A subgroup analysis in patients with acute myeloid leukemia (AML) was also performed. \u0000\u0000\u0000\u0000\u0000 There were 94 patients who met the study criteria. Of those, 29 patients had positive culture for fungus (30.82%): categorized as Aspergillus (19 patients; 65.51%) and Candida (10 patients; 34.49%). The mortality rate was significantly higher in the fungal infection group than the bacterial infection group (24.14% vs 6.15%; p 0.031). There were six factors in the final model predictive of fungal infection with one independent predictor: treatment regimen of Idarubicin plus Ara-C with an adjusted odds ratio of 5.188 (95% CI of 1.386, 19.419). A subgroup analysis for fungal infection in patients with AML showed that only the treatment regimen of Idarubicin plus Ara-C was a significant factor. Its adjusted odds ratio was 5.138 (95% CI of 1.156, 24.467). \u0000\u0000\u0000\u0000\u0000Treatment with idarubicin and Ara-C may increase the risk of fungal infection in acute leukemia patients with FN.\u0000\u0000","PeriodicalId":91228,"journal":{"name":"Clinical cancer drugs","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42147536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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