Many chemotherapeutic drugs induce oxidative stress by accelerating the accumulation of reactive oxygen species (ROS), which triggers the death of cancer cells and then causes severe DNA damage in cancer cells. Here, we proposed using a preclinical microfluidic model to evaluate the combination of doxorubicin and aspirin (DA) for anti-inflammatory therapy using patient-derived circulating tumor cell (CTC) clusters. The preclinical model could perform high-throughput screening of drug combinations and used valves to regulate media inflow for CTC cluster formation. We demonstrated that low-dose aspirin (445–500 mg/ml) and a suboptimal dose of doxorubicin (0.5 D) for seven days could produce higher killing efficacy and significantly reduced the proportion of cancer stem cells and colony-forming ability. Compared with the treatment with doxorubicin alone, the intracellular oxidative activity in the sample under combinatorial DA treatment was reduced, as demonstrated by the intensity of Calcein AM. We demonstrated that the treatment outcomes were mediated by the reduction of COX-2, which was associated with inflammation triggered by ROS. Overall, the preclinical model could be used as a proof of concept to demonstrate the efficacy of anti-inflammatory combinatorial therapies by influencing oxidative stress. Similar research could provide a basis for more DNA-related cancer treatment research in the future.
{"title":"Anti-inflammatory combinatorial therapy to enhance killing efficacy with patient-derived preclinical models","authors":"Jing Zhang, B. L. Khoo","doi":"10.3390/iecc2021-09204","DOIUrl":"https://doi.org/10.3390/iecc2021-09204","url":null,"abstract":"Many chemotherapeutic drugs induce oxidative stress by accelerating the accumulation of reactive oxygen species (ROS), which triggers the death of cancer cells and then causes severe DNA damage in cancer cells. Here, we proposed using a preclinical microfluidic model to evaluate the combination of doxorubicin and aspirin (DA) for anti-inflammatory therapy using patient-derived circulating tumor cell (CTC) clusters. The preclinical model could perform high-throughput screening of drug combinations and used valves to regulate media inflow for CTC cluster formation. We demonstrated that low-dose aspirin (445–500 mg/ml) and a suboptimal dose of doxorubicin (0.5 D) for seven days could produce higher killing efficacy and significantly reduced the proportion of cancer stem cells and colony-forming ability. Compared with the treatment with doxorubicin alone, the intracellular oxidative activity in the sample under combinatorial DA treatment was reduced, as demonstrated by the intensity of Calcein AM. We demonstrated that the treatment outcomes were mediated by the reduction of COX-2, which was associated with inflammation triggered by ROS. Overall, the preclinical model could be used as a proof of concept to demonstrate the efficacy of anti-inflammatory combinatorial therapies by influencing oxidative stress. Similar research could provide a basis for more DNA-related cancer treatment research in the future.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89773916","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}
S. Agelaki, Krystallia Gourlia, M. Markaki, C. Papadaki, K. Rounis, E. Vorrias, Elena Prokova, E. Lagoudaki, A. Koutsopoulos, I. Tsamardinos, D. Mavroudis
: Platinum-based chemotherapy (CT) is a standard treatment for lung cancer, however a variety of chemoresistance mechanisms can impair its efficacy. MicroRNAs (miRNAs) represent potential biomarkers for the prediction of treatment efficacy in non-small cell lung cancer (NSCLC). We herein used a bioinformatics approach to identify differentially expressed (DE) miRNAs associated with response to platinum-based CT in NSCLC. We identified 6 miRNAs targeting signaling molecules participating in biological pathways involved in cancer and drug resistance. In summary, we developed a 6-miRNA signature that potentially predicts the response to cisplatin in NSCLC and warrants further validation in clinical samples.
{"title":"MicroRNA Expression Analysis and Biological Pathways in Chemoresistant Non- Small Cell Lung Cancer","authors":"S. Agelaki, Krystallia Gourlia, M. Markaki, C. Papadaki, K. Rounis, E. Vorrias, Elena Prokova, E. Lagoudaki, A. Koutsopoulos, I. Tsamardinos, D. Mavroudis","doi":"10.3390/iecc2021-09206","DOIUrl":"https://doi.org/10.3390/iecc2021-09206","url":null,"abstract":": Platinum-based chemotherapy (CT) is a standard treatment for lung cancer, however a variety of chemoresistance mechanisms can impair its efficacy. MicroRNAs (miRNAs) represent potential biomarkers for the prediction of treatment efficacy in non-small cell lung cancer (NSCLC). We herein used a bioinformatics approach to identify differentially expressed (DE) miRNAs associated with response to platinum-based CT in NSCLC. We identified 6 miRNAs targeting signaling molecules participating in biological pathways involved in cancer and drug resistance. In summary, we developed a 6-miRNA signature that potentially predicts the response to cisplatin in NSCLC and warrants further validation in clinical samples.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90921876","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}
P. Peinado, Á. Andrades, Juan Sanjuan-Hidalgo, Jeffrey R. Haswell, J. Álvarez-Pérez, F. Slack, Pedro Medina Vico
The chromatin-remodeling complex SWI/SNF is the most mutated remodeler that is currently described in many tumor types. Traditionally, it has been associated with a tumor suppressive role, leading the cellular machinery towards differentiation pathways and DNA repair processes. ARID1A is the most mutated SWI/SNF subunit across all human malignancies. It is also considered as one of the top mutated genes in lung adenocarcinoma (LUAD) and an important driver gene. However, there is a lack of phenotypical studies that confirm the tumor suppressive role of ARID1A in LUAD. We have observed that ARID1A depletion in LUAD cell lines significantly impaired cell viability and promoted apoptosis. At first glance, these results contradicted its initially defined tumor suppressor status and could not be explained by synthetic lethal events involving other SWI/SNF subunits or driver genes. In addition, when we down-regulated ARID1A in a normal lung cell line, we did not see a significant reduction of cell viability, suggesting a tumor context dependency of ARID1A. Moreover, after performing RNA-seq in A549 after ARID1A-knockdown, we observed some up-regulated pathways related with apoptosis and genotoxic stress responses. We found that the depletion of ARID1A enhanced DNA damage in cells and triggered a severe ER stress response that promoted apoptosis. In addition, the protein levels of other subunits of the SWI/SNF complex decreased upon ARID1A, which could explain a decrease of the DNA repair processes. Overall, we conclude that some LUAD cell lines are dependent on ARID1A expression in a tumor-dependent manner. In those contexts, ARID1A loss triggers a DNA damage-induced apoptosis, which could open new therapeutic opportunities.
{"title":"ARID1A: The Good, the Bad and the Ugly.","authors":"P. Peinado, Á. Andrades, Juan Sanjuan-Hidalgo, Jeffrey R. Haswell, J. Álvarez-Pérez, F. Slack, Pedro Medina Vico","doi":"10.3390/iecc2021-09189","DOIUrl":"https://doi.org/10.3390/iecc2021-09189","url":null,"abstract":"The chromatin-remodeling complex SWI/SNF is the most mutated remodeler that is currently described in many tumor types. Traditionally, it has been associated with a tumor suppressive role, leading the cellular machinery towards differentiation pathways and DNA repair processes. ARID1A is the most mutated SWI/SNF subunit across all human malignancies. It is also considered as one of the top mutated genes in lung adenocarcinoma (LUAD) and an important driver gene. However, there is a lack of phenotypical studies that confirm the tumor suppressive role of ARID1A in LUAD. \u0000We have observed that ARID1A depletion in LUAD cell lines significantly impaired cell viability and promoted apoptosis. At first glance, these results contradicted its initially defined tumor suppressor status and could not be explained by synthetic lethal events involving other SWI/SNF subunits or driver genes. In addition, when we down-regulated ARID1A in a normal lung cell line, we did not see a significant reduction of cell viability, suggesting a tumor context dependency of ARID1A. Moreover, after performing RNA-seq in A549 after ARID1A-knockdown, we observed some up-regulated pathways related with apoptosis and genotoxic stress responses. We found that the depletion of ARID1A enhanced DNA damage in cells and triggered a severe ER stress response that promoted apoptosis. In addition, the protein levels of other subunits of the SWI/SNF complex decreased upon ARID1A, which could explain a decrease of the DNA repair processes. \u0000Overall, we conclude that some LUAD cell lines are dependent on ARID1A expression in a tumor-dependent manner. In those contexts, ARID1A loss triggers a DNA damage-induced apoptosis, which could open new therapeutic opportunities.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73490915","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}
Wai Yiu Tse, E. Maniati, Jun Wang, M. Lockley, Sarah Martin
{"title":"Identification of a novel regulator of FANCD2 mediated DNA Repair","authors":"Wai Yiu Tse, E. Maniati, Jun Wang, M. Lockley, Sarah Martin","doi":"10.3390/iecc2021-09200","DOIUrl":"https://doi.org/10.3390/iecc2021-09200","url":null,"abstract":"","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74325918","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}
W. Ramadan, M. Ayad, R. Hamoudi, A. Laham, V. Menon, L. Lozon, H. Abdu-Allah, A. El-Shorbagi, H. Tarazi, R. El-Awady
The last several years have witnessed a tremendous advance in the knowledge of DNA repair and cell cycle mechanisms for the purpose of increasing the treatment efficacy of radiotherapy and DNA damaging agents. Thereby, targeting DNA damage and repair pathways and cell cycle checkpoints become an attractive rationale to optimize treatment strategies through identifying new targets. However, the improved knowledge has increased the complexity of DNA damage response (DDR) and checkpoint pathways which extremely proved challenges in the development of cell cycle and DNA repair targeting drugs. To this end, a novel approach of synthesizing new compounds has been recently introduced which involved accommodating two chemical entities that target several molecules into a single structure. Here we combined 5-aminosalicylic acid and 4-thiazolinone, which both reported to affect DDR and cell cycle progression, in a single structural framework to generate two derivatives named HH32 and HH33. The transcriptomic, in silico, and in vitro analysis has been used to uncover the anti-cancer potential of these two compounds. Both compounds exhibited a high cytotoxic effect against a panel of eight cancer cell lines from different tissue origins and showed a low toxicity profile on normal cells compared to Doxorubicin. The in-silico molecular docking predicts a strong binding of the HH32 and HH33 to cell cycle regulators like CDC2-cyclin B, CDK2-cyclin A complexes, and retinoblastoma. Interestingly, the transcriptomic analysis revealed that DNA double-strand repair and cell cycle are the most affected pathways by HH33 compound. These findings were validated using in vitro models and demonstrated the induction of DNA double-strand breaks and the stimulation of ATM/ATR signaling pathway by HH32 and HH33. In addition to the potent effect of HH compounds on cell cycle progression mediated through upregulation of cyclin-dependent kinase inhibitors and downregulation of G2/M phase cell cycle markers which ultimately arrest the cells at G2/M phase and promote apoptosis. In conclusion, the pleiotropic biological effect of HH32 and HH33 compounds on cancer cells suggests the requirement for assessing their anti-cancer activities in preclinical models which may lead to a new area in the development of potentially therapeutic drugs.
{"title":"5-aminosalicylate–4-thiazolinone hybrid derivatives: A potent modulator of DNA damage response and G2/M cell cycle arrest via ATM/ATR pathway and Cyclin-CDK complex","authors":"W. Ramadan, M. Ayad, R. Hamoudi, A. Laham, V. Menon, L. Lozon, H. Abdu-Allah, A. El-Shorbagi, H. Tarazi, R. El-Awady","doi":"10.3390/iecc2021-09188","DOIUrl":"https://doi.org/10.3390/iecc2021-09188","url":null,"abstract":"The last several years have witnessed a tremendous advance in the knowledge of DNA repair and cell cycle mechanisms for the purpose of increasing the treatment efficacy of radiotherapy and DNA damaging agents. Thereby, targeting DNA damage and repair pathways and cell cycle checkpoints become an attractive rationale to optimize treatment strategies through identifying new targets. However, the improved knowledge has increased the complexity of DNA damage response (DDR) and checkpoint pathways which extremely proved challenges in the development of cell cycle and DNA repair targeting drugs. To this end, a novel approach of synthesizing new compounds has been recently introduced which involved accommodating two chemical entities that target several molecules into a single structure. Here we combined 5-aminosalicylic acid and 4-thiazolinone, which both reported to affect DDR and cell cycle progression, in a single structural framework to generate two derivatives named HH32 and HH33. The transcriptomic, in silico, and in vitro analysis has been used to uncover the anti-cancer potential of these two compounds. Both compounds exhibited a high cytotoxic effect against a panel of eight cancer cell lines from different tissue origins and showed a low toxicity profile on normal cells compared to Doxorubicin. The in-silico molecular docking predicts a strong binding of the HH32 and HH33 to cell cycle regulators like CDC2-cyclin B, CDK2-cyclin A complexes, and retinoblastoma. Interestingly, the transcriptomic analysis revealed that DNA double-strand repair and cell cycle are the most affected pathways by HH33 compound. These findings were validated using in vitro models and demonstrated the induction of DNA double-strand breaks and the stimulation of ATM/ATR signaling pathway by HH32 and HH33. In addition to the potent effect of HH compounds on cell cycle progression mediated through upregulation of cyclin-dependent kinase inhibitors and downregulation of G2/M phase cell cycle markers which ultimately arrest the cells at G2/M phase and promote apoptosis. In conclusion, the pleiotropic biological effect of HH32 and HH33 compounds on cancer cells suggests the requirement for assessing their anti-cancer activities in preclinical models which may lead to a new area in the development of potentially therapeutic drugs.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84878403","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}
Nucleotide excision repair (NER) is an essential DNA damage repair pathway that removes bulky DNA lesions formed by exposure to ultraviolet light, environmental toxins, and platinum (Pt)-based chemotherapeutic drugs that are a standard of care for many cancer types. Mutation or decreased NER gene expression in cancer correlates with improved patient survival after Pt-based chemotherapy. However, the impact of most missense mutations in NER genes is unknown, and few approaches exist to reliably identify nonrecurrent passenger mutations with functional consequences. In this study, a multidisciplinary strategy will be developed to predict, validate, and characterize NER-defective mutations in the essential NER scaffold protein Xeroderma Pigmentosum Complementation Group A (XPA). Computational analyses were used to score NER-deficient versus NER-proficient mutations for further study. Predicted NER-deficient XPA mutants are being expressed in human XPA-deficient cells and screened for both NER activity and cisplatin sensitivity. In-depth biophysical and structural studies are being implemented to elucidate mechanisms of dysfunction. Identifying NER-deficient mutations that may sensitize tumors to Pt-based chemotherapies represents a promising strategy to stratify patients for optimal treatment strategies.
{"title":"Developing a multidisciplinary strategy to interpret the impact of missense mutations in XPA on NER activity and cisplatin sensitivity","authors":"Alexandra M. Blee, Bian Li, J. Capra, W. Chazin","doi":"10.3390/iecc2021-09192","DOIUrl":"https://doi.org/10.3390/iecc2021-09192","url":null,"abstract":"Nucleotide excision repair (NER) is an essential DNA damage repair pathway that removes bulky DNA lesions formed by exposure to ultraviolet light, environmental toxins, and platinum (Pt)-based chemotherapeutic drugs that are a standard of care for many cancer types. Mutation or decreased NER gene expression in cancer correlates with improved patient survival after Pt-based chemotherapy. However, the impact of most missense mutations in NER genes is unknown, and few approaches exist to reliably identify nonrecurrent passenger mutations with functional consequences. In this study, a multidisciplinary strategy will be developed to predict, validate, and characterize NER-defective mutations in the essential NER scaffold protein Xeroderma Pigmentosum Complementation Group A (XPA). Computational analyses were used to score NER-deficient versus NER-proficient mutations for further study. Predicted NER-deficient XPA mutants are being expressed in human XPA-deficient cells and screened for both NER activity and cisplatin sensitivity. In-depth biophysical and structural studies are being implemented to elucidate mechanisms of dysfunction. Identifying NER-deficient mutations that may sensitize tumors to Pt-based chemotherapies represents a promising strategy to stratify patients for optimal treatment strategies.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89512555","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}
Glioblastoma (GBM) is a treatment refractory cancer of extreme unmet need which exhibits treatment resistance due to a subpopulation of GBM cancer stem cells which have constitutive DNA damage response activation driven by elevated replication stress (RS). RS response inhibition is potently cytotoxic to GSC, however mechanistic understanding will be key to biomarker discovery and successful clinical translation. We investigated response to combined ATR and PARP inhibition (CAiPi) to gain mechanistic insight and inform biomarker development. A panel of patient-derived GBM cell lines were cultured as stem enriched (GSCs) or stem depleted (bulk), to characterise response to combined ATR inhibition (VE821 5μM) and PARP inhibition (Olaparib 1μM), by CellTiter-Glo viability assay. Mechanistic investigations included immunofluorescence of 53BP1 nuclear bodies and DNA fibre analysis. Studies into the importance of PARP trapping included another PARPi Veliparib (1μM), and investigations into inhibition of origin firing used the CDK inhibitor Roscovitine. Responses to CAiPi in a panel of primary paired GBM GSCs vs differentiated progeny were heterogenous. CAiPi is selectively GSC cytotoxic in a subpopulation of tumours. DNA fibre analysis identified increased new origin firing with PARPi, which was correlated with increased PARP trapping. Inhibition of origin firing by exposure to roscovitine rescued the CAiPi cytotoxic phenotype, suggesting origin firing has an important role in selective GSC cytotoxicity. A population of treatment-sensitive GSCs with increased numbers of 53BP1 nuclear bodies in G1 phase with CAiPi were identified, indicative of under-replication of DNA in S phase. Selective GSC cytotoxicity is induced by CAiPi via dysregulation of replication, by both DNA under-replication resulting in DNA lesions, and the novel finding of increased new origin firing in GSC due to PARPi.
{"title":"Excessive new origin firing underlies selective glioma stem cell cytotoxicity induced by replication stress response inhibition","authors":"Emily Clough, K. Strathdee, R. Carruthers","doi":"10.3390/iecc2021-09187","DOIUrl":"https://doi.org/10.3390/iecc2021-09187","url":null,"abstract":"\u0000 \u0000 \u0000 Glioblastoma (GBM) is a treatment refractory cancer of extreme unmet need which exhibits treatment resistance due to a subpopulation of GBM cancer stem cells which have constitutive DNA damage response activation driven by elevated replication stress (RS). RS response inhibition is potently cytotoxic to GSC, however mechanistic understanding will be key to biomarker discovery and successful clinical translation.\u0000 We investigated response to combined ATR and PARP inhibition (CAiPi) to gain mechanistic insight and inform biomarker development.\u0000 \u0000 \u0000 \u0000 A panel of patient-derived GBM cell lines were cultured as stem enriched (GSCs) or stem depleted (bulk), to characterise response to combined ATR inhibition (VE821 5μM) and PARP inhibition (Olaparib 1μM), by CellTiter-Glo viability assay.\u0000 Mechanistic investigations included immunofluorescence of 53BP1 nuclear bodies and DNA fibre analysis. Studies into the importance of PARP trapping included another PARPi Veliparib (1μM), and investigations into inhibition of origin firing used the CDK inhibitor Roscovitine.\u0000 \u0000 \u0000 \u0000 Responses to CAiPi in a panel of primary paired GBM GSCs vs differentiated progeny were heterogenous. CAiPi is selectively GSC cytotoxic in a subpopulation of tumours. DNA fibre analysis identified increased new origin firing with PARPi, which was correlated with increased PARP trapping. Inhibition of origin firing by exposure to roscovitine rescued the CAiPi cytotoxic phenotype, suggesting origin firing has an important role in selective GSC cytotoxicity.\u0000 A population of treatment-sensitive GSCs with increased numbers of 53BP1 nuclear bodies in G1 phase with CAiPi were identified, indicative of under-replication of DNA in S phase.\u0000 \u0000 \u0000 \u0000 Selective GSC cytotoxicity is induced by CAiPi via dysregulation of replication, by both DNA under-replication resulting in DNA lesions, and the novel finding of increased new origin firing in GSC due to PARPi.\u0000 \u0000 \u0000 \u0000","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76398579","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}
K. Salmina, Felikss Rumnieks, N. Vainshelbaum, D. Pjanova, J. Erenpreisa
{"title":"Role of Mitotic slippage in cancer resistance and DNA damage response in the MDA-MB-231-DOX-Treated Cells","authors":"K. Salmina, Felikss Rumnieks, N. Vainshelbaum, D. Pjanova, J. Erenpreisa","doi":"10.3390/iecc2021-09214","DOIUrl":"https://doi.org/10.3390/iecc2021-09214","url":null,"abstract":"","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86066644","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}
Amy Gibson, V. Morales, K. Bianchi, E. Crosbie, G. Ficz, Sarah Martin
{"title":"Loss of MLH1 regulates a metabolic phenotype in endometrial cancer","authors":"Amy Gibson, V. Morales, K. Bianchi, E. Crosbie, G. Ficz, Sarah Martin","doi":"10.3390/iecc2021-09196","DOIUrl":"https://doi.org/10.3390/iecc2021-09196","url":null,"abstract":"","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91137620","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}
M. Walter, E. Homan, Tobias Koolmeister, I. Almlöf, T. Helleday, P. Herr
Here we present the characterisation of the so far unstudied NUDIX hydrolase family member NUDT22. We previously identified a unique hydrolase activity of NUDT22 towards UDP-glucose from a family-wide biochemical substrate screen. UDP-glucose hydrolysis results in the production of uridine monophosphate (UMP) and glucose 1-phosphate (G-1-P). We furthermore solved the first crystal structure of NUDT22 in complex with its substrate UDP-glucose [1]. Our mechanistic studies reveal increased replication stress in NUDT22 deficient cells which can be rescued by nucleoside supplementation. We therefore propose the discovery of a novel NUDT22-mediated pyrimidine salvage pathway.Increased replication rates resulting in replication stress is a hallmark of cancer cells and NUDT22 gene expression alterations are present in several cancer tissues, which makes it an interesting new target for the development of small molecule inhibitors for uses in cancer.We employed our NUDT22 crystal structure to perform an in silico docking screen on available small molecule libraries to identify starting points for the development of first-in-class NUDT22 inhibitors. Chemically optimised NUDT22 inhibitors are currently being validated in biochemical assays, cellular target engagement assays, and their cellular activity is being assessed in vitro. [1] M. Carter et al., "Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold," Structure, vol. 26, no. 2, pp. 295-+, Feb 2018, doi: 10.1016/j.str.2018.01.004.
在这里，我们介绍了迄今为止尚未研究的NUDIX水解酶家族成员NUDT22的特征。我们之前从全家族生化底物筛选中鉴定出NUDT22对udp -葡萄糖的独特水解酶活性。udp -葡萄糖水解产生尿苷单磷酸(UMP)和葡萄糖1-磷酸(G-1-P)。我们进一步解决了NUDT22与底物udp -葡萄糖[1]配合物的第一个晶体结构。我们的机制研究表明，NUDT22缺陷细胞的复制应激增加，可以通过补充核苷来挽救。因此，我们提出发现一种新的nudt22介导的嘧啶回收途径。增加的复制速率导致复制应激是癌细胞的一个标志，NUDT22基因表达改变存在于几种癌症组织中，这使得它成为开发用于癌症的小分子抑制剂的一个有趣的新靶点。我们利用我们的NUDT22晶体结构对可用的小分子文库进行硅对接筛选，以确定开发一流NUDT22抑制剂的起点。化学优化的NUDT22抑制剂目前正在生化分析、细胞靶标接合分析中进行验证，并且正在体外评估其细胞活性。[10] M. Carter等人，“人类NUDT22是一种呈现独特结构折叠的udp -葡萄糖/半乳糖水解酶”，《结构》，第26卷，第2期。2, pp. 295-+， 2018年2月，doi: 10.1016/j.s r.2018.01.004。
{"title":"Development of small molecule NUDT22 inhibitors for uses in cancer.","authors":"M. Walter, E. Homan, Tobias Koolmeister, I. Almlöf, T. Helleday, P. Herr","doi":"10.3390/iecc2021-09197","DOIUrl":"https://doi.org/10.3390/iecc2021-09197","url":null,"abstract":"Here we present the characterisation of the so far unstudied NUDIX hydrolase family member NUDT22. We previously identified a unique hydrolase activity of NUDT22 towards UDP-glucose from a family-wide biochemical substrate screen. UDP-glucose hydrolysis results in the production of uridine monophosphate (UMP) and glucose 1-phosphate (G-1-P). We furthermore solved the first crystal structure of NUDT22 in complex with its substrate UDP-glucose [1]. Our mechanistic studies reveal increased replication stress in NUDT22 deficient cells which can be rescued by nucleoside supplementation. We therefore propose the discovery of a novel NUDT22-mediated pyrimidine salvage pathway.Increased replication rates resulting in replication stress is a hallmark of cancer cells and NUDT22 gene expression alterations are present in several cancer tissues, which makes it an interesting new target for the development of small molecule inhibitors for uses in cancer.We employed our NUDT22 crystal structure to perform an in silico docking screen on available small molecule libraries to identify starting points for the development of first-in-class NUDT22 inhibitors. Chemically optimised NUDT22 inhibitors are currently being validated in biochemical assays, cellular target engagement assays, and their cellular activity is being assessed in vitro. \u0000[1] M. Carter et al., \"Human NUDT22 Is a UDP-Glucose/Galactose Hydrolase Exhibiting a Unique Structural Fold,\" Structure, vol. 26, no. 2, pp. 295-+, Feb 2018, doi: 10.1016/j.str.2018.01.004.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82592440","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：