In non-small-cell lung cancer (NSCLC)-the leading cause of cancer death worldwide-about 10-20% harbor mutations in epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Although treatment with EGFR tyrosine kinase inhibitors (TKIs) had shown promise, drug resistance has been the most important determinant limiting its success. We recently studied the mechanism by which a small subset of cells remains viable after EGFR inhibition, despite cell death in the vast majority. Our study demonstrates that EGFR inhibition in lung cancer cells generates a drug-tolerant subpopulation by blocking AKT activity and thus inactivating Ets-1 function. The remaining cells enter a dormant, non-dividing state because of the inhibited transactivation of Ets-1 target genes cyclins D1, D3, and E2. Moreover, Ets-1 inactivation inhibits transcription of dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated, which combines with c-Src to renew activation of the Ras/MAPK pathway, causing increased cell survival by accelerating Bim protein turnover. These observations may explain why a small subset of quiescent cells can tolerate TKIs, leading to acquired drug resistance. In this editorial, we discuss how changes in intrinsic cell signaling open a new avenue to drug resistance in NSCLCs after EGFR inhibition. We also comment on combined treatment with TKI and MEK inhibitor to reduce the probability of emergent resistance to EGFR TKIs.
{"title":"EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity","authors":"J. Phuchareon, F. McCormick, D. Eisele, O. Tetsu","doi":"10.14800/CCM.1045","DOIUrl":"https://doi.org/10.14800/CCM.1045","url":null,"abstract":"In non-small-cell lung cancer (NSCLC)-the leading cause of cancer death worldwide-about 10-20% harbor mutations in epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Although treatment with EGFR tyrosine kinase inhibitors (TKIs) had shown promise, drug resistance has been the most important determinant limiting its success. We recently studied the mechanism by which a small subset of cells remains viable after EGFR inhibition, despite cell death in the vast majority. Our study demonstrates that EGFR inhibition in lung cancer cells generates a drug-tolerant subpopulation by blocking AKT activity and thus inactivating Ets-1 function. The remaining cells enter a dormant, non-dividing state because of the inhibited transactivation of Ets-1 target genes cyclins D1, D3, and E2. Moreover, Ets-1 inactivation inhibits transcription of dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated, which combines with c-Src to renew activation of the Ras/MAPK pathway, causing increased cell survival by accelerating Bim protein turnover. These observations may explain why a small subset of quiescent cells can tolerate TKIs, leading to acquired drug resistance. In this editorial, we discuss how changes in intrinsic cell signaling open a new avenue to drug resistance in NSCLCs after EGFR inhibition. We also comment on combined treatment with TKI and MEK inhibitor to reduce the probability of emergent resistance to EGFR TKIs.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"293 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77920751","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}
Aldehyde dehydrogenase (ALDH) is a ubiquitous intracellular enzyme that catalyzes the irreversible oxidation of a variety of cellular aldehydes. High levels of ALDH activity, involving several isoforms of ALDH (ALDH1A1, ALDH1A2, ALDH1A3 and ALDH8A1), have been proposed as a common feature of stem cells. Adult hematopoietic, neural, and cancer stem cells have been reported to have high ALDH activity, decreased using Aldefluor, a fluorogenic substrate for ALDH. This activity has been attributed to ALDH1A1 expression, an enzyme that has been suggested to regulate stem cell function, including self-protection, differentiation, and expansion of stem cell populations. Recently, it was found that, in the liver, ALDH1A1 was expressed in almost all normal hepatocytes. However, ALDH1A1-overexpressing cells in hepatocellular carcinoma were not co-expressed with putative cancer stem cell markers CD133, CD13, CD90, BMI1, and EpCAM. In this respect, cancer stem cell target therapy related to ALDH1A1 should proceed with some caution; more detailed studies are needed because of this off-target toxicology. However, the subpopulation of cancer stem cells does represent a potential therapeutic target for poor-prognostic, treatment–resistant and recurrent cancer.
{"title":"The role of aldehyde dehydrogenase 1A1 in stem cells and cancer stem cells","authors":"H. Tomita, Kaori Tanaka, K. Hisamatsu, A. Hara","doi":"10.14800/CCM.1064","DOIUrl":"https://doi.org/10.14800/CCM.1064","url":null,"abstract":"Aldehyde dehydrogenase (ALDH) is a ubiquitous intracellular enzyme that catalyzes the irreversible oxidation of a variety of cellular aldehydes. High levels of ALDH activity, involving several isoforms of ALDH (ALDH1A1, ALDH1A2, ALDH1A3 and ALDH8A1), have been proposed as a common feature of stem cells. Adult hematopoietic, neural, and cancer stem cells have been reported to have high ALDH activity, decreased using Aldefluor, a fluorogenic substrate for ALDH. This activity has been attributed to ALDH1A1 expression, an enzyme that has been suggested to regulate stem cell function, including self-protection, differentiation, and expansion of stem cell populations. Recently, it was found that, in the liver, ALDH1A1 was expressed in almost all normal hepatocytes. However, ALDH1A1-overexpressing cells in hepatocellular carcinoma were not co-expressed with putative cancer stem cell markers CD133, CD13, CD90, BMI1, and EpCAM. In this respect, cancer stem cell target therapy related to ALDH1A1 should proceed with some caution; more detailed studies are needed because of this off-target toxicology. However, the subpopulation of cancer stem cells does represent a potential therapeutic target for poor-prognostic, treatment–resistant and recurrent cancer.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82848162","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}
Epstein-Barr virus (EBV) is closely associated with certain lymphoid and epithelial malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). In the tumor cells, the virus persists in a tight latency, expressing a limited number of latent proteins. Reactivation of EBV lytic cycle from latency leads to expression of many more viral lytic proteins which may provide potential therapeutic targets for the EBV-associated cancers. Histone deacetylase (HDAC) inhibitors belong to an emerging class of anti-cancer agents which work through acetylation of different histone and non-histone proteins in cancer cells. Our previous work showed that various pan-HDAC inhibitors, which inhibit eleven HDAC isoforms, can preferentially reactivate EBV lytic cycle in EBV-positive epithelial rather than lymphoid cancers and mediate enhanced killing of EBV-positive NPC and GC cells through augmentation of apoptotic cell death. Recently, we found that a selective class I HDAC inhibitor, romidepsin, can potently induce EBV lytic cycle in NPC and GC cells and confer susceptibility of the induced cells to killing by an anti-viral agent, ganciclovir, in vitro and in vivo . The reactivation of EBV lytic cycle by romidepsin is related to the inhibition of HDAC-1, -2 and -3 isoforms and the activation of PKC-d. Interestingly, our current findings suggest that acetylation of non-histone proteins might also play a role in the regulation of EBV lytic cycle upon HDAC inhibition. In this review, we discuss our recent findings on the mechanisms of EBV lytic cycle reactivation and propose possible strategies in using HDAC inhibitors for the treatment of EBV-associated cancers.
{"title":"Reactivation of Epstein-Barr virus lytic cycle by histone deacetylase inhibitors","authors":"K. Hui, A. Chiang","doi":"10.14800/CCM.1033","DOIUrl":"https://doi.org/10.14800/CCM.1033","url":null,"abstract":"Epstein-Barr virus (EBV) is closely associated with certain lymphoid and epithelial malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). In the tumor cells, the virus persists in a tight latency, expressing a limited number of latent proteins. Reactivation of EBV lytic cycle from latency leads to expression of many more viral lytic proteins which may provide potential therapeutic targets for the EBV-associated cancers. Histone deacetylase (HDAC) inhibitors belong to an emerging class of anti-cancer agents which work through acetylation of different histone and non-histone proteins in cancer cells. Our previous work showed that various pan-HDAC inhibitors, which inhibit eleven HDAC isoforms, can preferentially reactivate EBV lytic cycle in EBV-positive epithelial rather than lymphoid cancers and mediate enhanced killing of EBV-positive NPC and GC cells through augmentation of apoptotic cell death. Recently, we found that a selective class I HDAC inhibitor, romidepsin, can potently induce EBV lytic cycle in NPC and GC cells and confer susceptibility of the induced cells to killing by an anti-viral agent, ganciclovir, in vitro and in vivo . The reactivation of EBV lytic cycle by romidepsin is related to the inhibition of HDAC-1, -2 and -3 isoforms and the activation of PKC-d. Interestingly, our current findings suggest that acetylation of non-histone proteins might also play a role in the regulation of EBV lytic cycle upon HDAC inhibition. In this review, we discuss our recent findings on the mechanisms of EBV lytic cycle reactivation and propose possible strategies in using HDAC inhibitors for the treatment of EBV-associated cancers.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89172202","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}
The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing. NAFLD affects the health of one-third of the world’s population in forms that range from simple steatosis to hepatocellular injury, inflammation, fibrosis, liver cirrhosis and hepatocarcinoma. Oxidative stress in the progression of NAFLD to hepatocarcinoma is gaining increasing attention. Sustained and excessive reactive oxygen species (ROS), which lead to oxidative stress, are involved in all pathophysiological stages of NAFLD and contribute to the occurrence of hepatocarcinoma. Antioxidants in natural plant extracts that activate nuclear factor related to E2 factor 2 (Nrf2) can effectively suppress the progression. The cellular anti-oxidative system has great importance in the prevention and reversal of NAFLD. This review summarizes the current knowledge of the involvement of oxidative stress in NAFLD to hepatocarcinoma.
{"title":"ROS correlates intimately with the progression of non-alcoholic fatty liver disease to hepatocarcinoma","authors":"Yuan Yan, Jie Li, Lei Dong","doi":"10.14800/CCM.1044","DOIUrl":"https://doi.org/10.14800/CCM.1044","url":null,"abstract":"The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing. NAFLD affects the health of one-third of the world’s population in forms that range from simple steatosis to hepatocellular injury, inflammation, fibrosis, liver cirrhosis and hepatocarcinoma. Oxidative stress in the progression of NAFLD to hepatocarcinoma is gaining increasing attention. Sustained and excessive reactive oxygen species (ROS), which lead to oxidative stress, are involved in all pathophysiological stages of NAFLD and contribute to the occurrence of hepatocarcinoma. Antioxidants in natural plant extracts that activate nuclear factor related to E2 factor 2 (Nrf2) can effectively suppress the progression. The cellular anti-oxidative system has great importance in the prevention and reversal of NAFLD. This review summarizes the current knowledge of the involvement of oxidative stress in NAFLD to hepatocarcinoma.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91095896","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}
V. Hanušová, L. Skálová, M. Ambroz, V. Králová, L. Langhansová, P. Matoušková
Essential oil from leaves of Myrica rubra (MEO), a subtropical Asian fruit tree with traditional use in folk medicines, had significant antiproliferative effect in several intestinal cancer cell lines. In present study, we tested the influence of MEO and its most effective compounds α-humulene and trans-nerolidol on the cell adhesion, expression of adhesion molecules (ICAM-1; E-cadherin; β-catenin) and apoptotic molecules (NF-κB, caspases) in colorectal cancer cell line HT29. All parameters were followed up and compared in presence or absence of pro-inflammatory agent TNFα. The results showed that MEO was able to decrease adhesion of colon cancer HT29 cells to collagen. Furthermore MEO, α-humulene and trans -nerolidol significantly suppressed adhesion of TNFα-induced cells probably due to down-regulation of ICAM-1. Moreover, MEO and α-humulene could diminish tumor invasion and metastasis via up-regulation of E-cadherin. In presence of TNFα, MEO and trans- nerolidol decreased activation (phosphorylation) of NF-κB, increased activity of caspases and by this way induced apoptosis of cancer cells. More pronounced effects of MEO than those of α-humulene and trans -nerolidol indicate synergism and/or contribution of other components.
{"title":"The effect of Myrica rubra essential oil and its components α-humulene and trans-nerolidol on adhesion and apoptosis of colorectal cancer cells","authors":"V. Hanušová, L. Skálová, M. Ambroz, V. Králová, L. Langhansová, P. Matoušková","doi":"10.14800/CCM.1058","DOIUrl":"https://doi.org/10.14800/CCM.1058","url":null,"abstract":"Essential oil from leaves of Myrica rubra (MEO), a subtropical Asian fruit tree with traditional use in folk medicines, had significant antiproliferative effect in several intestinal cancer cell lines. In present study, we tested the influence of MEO and its most effective compounds α-humulene and trans-nerolidol on the cell adhesion, expression of adhesion molecules (ICAM-1; E-cadherin; β-catenin) and apoptotic molecules (NF-κB, caspases) in colorectal cancer cell line HT29. All parameters were followed up and compared in presence or absence of pro-inflammatory agent TNFα. The results showed that MEO was able to decrease adhesion of colon cancer HT29 cells to collagen. Furthermore MEO, α-humulene and trans -nerolidol significantly suppressed adhesion of TNFα-induced cells probably due to down-regulation of ICAM-1. Moreover, MEO and α-humulene could diminish tumor invasion and metastasis via up-regulation of E-cadherin. In presence of TNFα, MEO and trans- nerolidol decreased activation (phosphorylation) of NF-κB, increased activity of caspases and by this way induced apoptosis of cancer cells. More pronounced effects of MEO than those of α-humulene and trans -nerolidol indicate synergism and/or contribution of other components.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82331889","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}
A. Barsotti, M. Ryskin, Kung Pei-Pei, D. Verhelle, R. A. Rollins
Epigenetic alterations are an important hallmark of cancer, and the enzymes that modify histone tails have emerged as attractive drug targets. The histone methyltransferase EZH2 is the catalytic subunit of PRC2, a highly conserved protein complex that regulates gene expression by methylating lysine 27 on histone H3. EZH2 is frequently overexpressed in cancer, and oncogenic gain-of-function mutations have been identified in both hematological malignancies and solid tumors. In cancer cells, the aberrant activity of the enzyme contributes to tumorigenesis by altering cell fate decisions and regulating pathways involved in proliferation, differentiation, and cell migration. Early validation efforts relied on the use of RNAi technology and non-specific small molecule inhibitors to down-regulate EZH2 and destabilize the PRC2 complex. The discovery of catalytic inhibitors of EZH2 has provided an invaluable tool for further elucidating the role of this enzyme in cancer, and preclinical studies in EZH2-mutant non-Hodgkin lymphoma have driven the clinical development of these agents. This review focuses on the use of catalytic small molecule inhibitors to identify solid tumor indications that are dependent on aberrant EZH2 methyltransferase activity. The emerging data suggests that EZH2 inhibitors will have therapeutic potential that extends beyond hematological malignancies to the solid tumor setting.
{"title":"EZH2 as a therapeutic target in solid tumors","authors":"A. Barsotti, M. Ryskin, Kung Pei-Pei, D. Verhelle, R. A. Rollins","doi":"10.14800/CCM.1024","DOIUrl":"https://doi.org/10.14800/CCM.1024","url":null,"abstract":"Epigenetic alterations are an important hallmark of cancer, and the enzymes that modify histone tails have emerged as attractive drug targets. The histone methyltransferase EZH2 is the catalytic subunit of PRC2, a highly conserved protein complex that regulates gene expression by methylating lysine 27 on histone H3. EZH2 is frequently overexpressed in cancer, and oncogenic gain-of-function mutations have been identified in both hematological malignancies and solid tumors. In cancer cells, the aberrant activity of the enzyme contributes to tumorigenesis by altering cell fate decisions and regulating pathways involved in proliferation, differentiation, and cell migration. Early validation efforts relied on the use of RNAi technology and non-specific small molecule inhibitors to down-regulate EZH2 and destabilize the PRC2 complex. The discovery of catalytic inhibitors of EZH2 has provided an invaluable tool for further elucidating the role of this enzyme in cancer, and preclinical studies in EZH2-mutant non-Hodgkin lymphoma have driven the clinical development of these agents. This review focuses on the use of catalytic small molecule inhibitors to identify solid tumor indications that are dependent on aberrant EZH2 methyltransferase activity. The emerging data suggests that EZH2 inhibitors will have therapeutic potential that extends beyond hematological malignancies to the solid tumor setting.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80462186","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}
We recently reported a study on the functional and clinicopathological significance of mitogen-activated protein kinase (MAPK)15 overexpression in patients with gastric cancer. Our data suggest that patients who overexpress MAPK15 in normal or premalignant stomach tissues may progress to invasive cancer [1] . In this research highlight, we summarize three features of MAPK15 as a potential target for treating gastric cancer. MAPK15 is specifically overexpressed in gastric cancers but not normal tissues. MAPK15 is involved in cell proliferation and tumorigenesis by regulating at least three signal pathways, such as c-Jun activity, telomerase activity, and autophagy. In addition, MAPK15 also has structural potential for development of a specific inhibitor. Based on these observations, MAPK15 may be a novel therapeutic target for gastric cancer.
{"title":"MAPK15 is an attractive therapeutic target for gastric cancer","authors":"Dong-Hao Jin, Joobae Park, Duk-Hwan Kim","doi":"10.14800/CCM.1006","DOIUrl":"https://doi.org/10.14800/CCM.1006","url":null,"abstract":"We recently reported a study on the functional and clinicopathological significance of mitogen-activated protein kinase (MAPK)15 overexpression in patients with gastric cancer. Our data suggest that patients who overexpress MAPK15 in normal or premalignant stomach tissues may progress to invasive cancer [1] . In this research highlight, we summarize three features of MAPK15 as a potential target for treating gastric cancer. MAPK15 is specifically overexpressed in gastric cancers but not normal tissues. MAPK15 is involved in cell proliferation and tumorigenesis by regulating at least three signal pathways, such as c-Jun activity, telomerase activity, and autophagy. In addition, MAPK15 also has structural potential for development of a specific inhibitor. Based on these observations, MAPK15 may be a novel therapeutic target for gastric cancer.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87190187","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}
We investigated possible conditions or drugs that might enhance the sensitivity of anti-mitotic drug-resistant cancer cells. We particularly focused on identifying mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells. Our approach utilized repositioning drugs, which are already used in clinics, because once their sensitization mechanisms on resistant cancer cells are known, they would be readily applied without further toxicity studies. Selenium-derived drugs such as selenate, selenite, selenomethionine (SeMet), methyl-selenocysteine (MSC), and methaneselenic acid (MSA) have been shown to have anti-cancer properties clinically. The type of selenium-derived drug that can specifically sensitize P-gp-overexpressing resistant KBV20C cancer cells was investigated for further application in the clinical settings. We recently reported five selenium-derived drugs that could sensitize both resistant KBV20C and KB parent sensitive cancer cells without P-gp inhibition. Among these five drugs, our study highlights the unprecedented finding of the selective sensitization ability of selenate against P-gp-overexpressed resistant KBV20C cells. Detailed analysis indicates that selenate is a resistant cancer cell-specific sensitizing drug that increases apoptosis via G2-phase cell cycle arrest. These results may help improve chemotherapeutic treatments based on selenium-derived drugs for cancer patients who develop resistance to anti-mitotic drugs.
{"title":"A single treatment of Selenate, a repositioning drug, specifically sensitizes P-gp-overexpressing resistant cancer cells","authors":"Sungpil Yoon","doi":"10.14800/CCM.957","DOIUrl":"https://doi.org/10.14800/CCM.957","url":null,"abstract":"We investigated possible conditions or drugs that might enhance the sensitivity of anti-mitotic drug-resistant cancer cells. We particularly focused on identifying mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells. Our approach utilized repositioning drugs, which are already used in clinics, because once their sensitization mechanisms on resistant cancer cells are known, they would be readily applied without further toxicity studies. Selenium-derived drugs such as selenate, selenite, selenomethionine (SeMet), methyl-selenocysteine (MSC), and methaneselenic acid (MSA) have been shown to have anti-cancer properties clinically. The type of selenium-derived drug that can specifically sensitize P-gp-overexpressing resistant KBV20C cancer cells was investigated for further application in the clinical settings. We recently reported five selenium-derived drugs that could sensitize both resistant KBV20C and KB parent sensitive cancer cells without P-gp inhibition. Among these five drugs, our study highlights the unprecedented finding of the selective sensitization ability of selenate against P-gp-overexpressed resistant KBV20C cells. Detailed analysis indicates that selenate is a resistant cancer cell-specific sensitizing drug that increases apoptosis via G2-phase cell cycle arrest. These results may help improve chemotherapeutic treatments based on selenium-derived drugs for cancer patients who develop resistance to anti-mitotic drugs.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89018023","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}
Given the role and relevance of the heterogeneity hallmark in cancer, a current need is to advance the knowledge of the network dynamics building the complex architecture underlying the relationships between cell sub-populations. This step would shed light over obscure mechanisms such as acquired resistance to drugs, for instance. Network medicine has established itself as a systems integrative approach that leverages on the interpretation offered by community-like behavior of bio-entities and clinical variables. Translated over cell sub-population cells, there is a strong case for deciphering cooperative versus antagonist network dynamics in order to determine better therapeutic strategies.
{"title":"Cancer hallmarks through the network lens","authors":"E. Capobianco","doi":"10.14800/CCM.943","DOIUrl":"https://doi.org/10.14800/CCM.943","url":null,"abstract":"Given the role and relevance of the heterogeneity hallmark in cancer, a current need is to advance the knowledge of the network dynamics building the complex architecture underlying the relationships between cell sub-populations. This step would shed light over obscure mechanisms such as acquired resistance to drugs, for instance. Network medicine has established itself as a systems integrative approach that leverages on the interpretation offered by community-like behavior of bio-entities and clinical variables. Translated over cell sub-population cells, there is a strong case for deciphering cooperative versus antagonist network dynamics in order to determine better therapeutic strategies.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77109166","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}
H. Niwa, Y. Maeyama, Shojiro Kikuchi, H. Kawaguchi, T. Daimon, Y. Furuya, Hiroshi Ito, N. Mizuno, M. Otsu, H. Yasuhara, M. Sasako
Scirrhous gastric cancer (SGC) is highly resistant to treatment and has a poor prognosis. Tumor stromal cells are considered to play vital roles in the development of SGC. However, interactions between cancer cells and stromal cells are poorly understood. We evaluated the importance of direct contact between cancer cells and stromal cells in vitro . We obtained gastric cancer-associated stromal cells (GCSCs) and normal gastric stromal cells (GSCs) from six patients. We co-cultured these cells with MKN45 solid-type gastric cancer and HSC43 SGC cells, respectively, for 7 days. Both gastric cancer cell lines were labeled with fluorescent protein to distinguish them from stromal cells in culture. We used two co-culture models: direct contact (GCSCs and GSCs), in which cancer cells and stromal cells were mixed, and indirect contact (GCSCs only), in which cells were separated by cell culture inserts. We also compared the gene expression profiles of GCSCs and GSCs by microarray assays. The cell growth rate was significantly higher in the direct-contact GCSC model compared with that in monocultured cells in MKN45, but not in HSC43 cells. For either cell line, there was no significant difference in growth rates between indirect GCSC co-cultures and monocultures, and no difference between direct or indirect GSC co-cultures and monocultures. In terms of gene expression, fibroblast growth factor 9, which has an anti-apoptotic effect on gastric cancer cells, was more up-regulated in GCSCs than in GSCs. Flow cytometry revealed no difference between GCSCs and GSCs in terms of marker expression. In conclusion, although stromal cells can influence the growth of gastric cancer cells, our results suggest that the impacts of interactions with stromal cells might vary according to the specific characteristics of the cancer cells.
{"title":"Impacts of cancer-associated stromal cells on growth of human gastric cancer cell lines","authors":"H. Niwa, Y. Maeyama, Shojiro Kikuchi, H. Kawaguchi, T. Daimon, Y. Furuya, Hiroshi Ito, N. Mizuno, M. Otsu, H. Yasuhara, M. Sasako","doi":"10.14800/CCM.921","DOIUrl":"https://doi.org/10.14800/CCM.921","url":null,"abstract":"Scirrhous gastric cancer (SGC) is highly resistant to treatment and has a poor prognosis. Tumor stromal cells are considered to play vital roles in the development of SGC. However, interactions between cancer cells and stromal cells are poorly understood. We evaluated the importance of direct contact between cancer cells and stromal cells in vitro . We obtained gastric cancer-associated stromal cells (GCSCs) and normal gastric stromal cells (GSCs) from six patients. We co-cultured these cells with MKN45 solid-type gastric cancer and HSC43 SGC cells, respectively, for 7 days. Both gastric cancer cell lines were labeled with fluorescent protein to distinguish them from stromal cells in culture. We used two co-culture models: direct contact (GCSCs and GSCs), in which cancer cells and stromal cells were mixed, and indirect contact (GCSCs only), in which cells were separated by cell culture inserts. We also compared the gene expression profiles of GCSCs and GSCs by microarray assays. The cell growth rate was significantly higher in the direct-contact GCSC model compared with that in monocultured cells in MKN45, but not in HSC43 cells. For either cell line, there was no significant difference in growth rates between indirect GCSC co-cultures and monocultures, and no difference between direct or indirect GSC co-cultures and monocultures. In terms of gene expression, fibroblast growth factor 9, which has an anti-apoptotic effect on gastric cancer cells, was more up-regulated in GCSCs than in GSCs. Flow cytometry revealed no difference between GCSCs and GSCs in terms of marker expression. In conclusion, although stromal cells can influence the growth of gastric cancer cells, our results suggest that the impacts of interactions with stromal cells might vary according to the specific characteristics of the cancer cells.","PeriodicalId":9576,"journal":{"name":"Cancer cell & microenvironment","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2015-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75934742","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：