Pub Date : 2023-04-12eCollection Date: 2023-01-01DOI: 10.20517/cdr.2022.127
Sandra Martínez-Martín, Marie-Eve Beaulieu, Laura Soucek
MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.
{"title":"Targeting MYC-driven lymphoma: lessons learned and future directions.","authors":"Sandra Martínez-Martín, Marie-Eve Beaulieu, Laura Soucek","doi":"10.20517/cdr.2022.127","DOIUrl":"10.20517/cdr.2022.127","url":null,"abstract":"<p><p>MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.
{"title":"Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance.","authors":"Ramesh Butti, Ashwini Khaladkar, Priya Bhardwaj, Gopinath Prakasam","doi":"10.20517/cdr.2022.72","DOIUrl":"10.20517/cdr.2022.72","url":null,"abstract":"<p><p>The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-03-15eCollection Date: 2023-01-01DOI: 10.20517/cdr.2022.108
Sylvain Garciaz, Thomas Miller, Yves Collette, Norbert Vey
The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.
{"title":"Targeting regulated cell death pathways in acute myeloid leukemia.","authors":"Sylvain Garciaz, Thomas Miller, Yves Collette, Norbert Vey","doi":"10.20517/cdr.2022.108","DOIUrl":"10.20517/cdr.2022.108","url":null,"abstract":"<p><p>The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9317815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leonhard H F Köhler, Sebastian Reich, Maria Yusenko, Karl-Heinz Klempnauer, Gerrit Begemann, Rainer Schobert, Bernhard Biersack
Aim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo. Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.
{"title":"Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities.","authors":"Leonhard H F Köhler, Sebastian Reich, Maria Yusenko, Karl-Heinz Klempnauer, Gerrit Begemann, Rainer Schobert, Bernhard Biersack","doi":"10.20517/cdr.2022.90","DOIUrl":"https://doi.org/10.20517/cdr.2022.90","url":null,"abstract":"<p><p><b>Aim:</b> Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. <b>Methods:</b> 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. <b>Results:</b> Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation <i>in vivo</i>. <b>Conclusion:</b> The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9317813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).
{"title":"How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?","authors":"Salvatore Perrone, Tiziana Ottone, Nadezda Zhdanovskaya, Matteo Molica","doi":"10.20517/cdr.2022.130","DOIUrl":"https://doi.org/10.20517/cdr.2022.130","url":null,"abstract":"<p><p>FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1<sup>st</sup> and 2<sup>nd</sup> generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meri Muminovic, Carlos Rodrigo Carracedo Uribe, Andres Alvarez-Pinzon, Khine Shan, Luis E Raez
Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.
{"title":"Importance of <i>ROS1</i> gene fusions in non-small cell lung cancer.","authors":"Meri Muminovic, Carlos Rodrigo Carracedo Uribe, Andres Alvarez-Pinzon, Khine Shan, Luis E Raez","doi":"10.20517/cdr.2022.105","DOIUrl":"https://doi.org/10.20517/cdr.2022.105","url":null,"abstract":"Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aim: Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). Methods: miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. Results: MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. Conclusion: This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.
{"title":"miR-16-5p enhances sensitivity to RG7388 through targeting <i>PPM1D</i> expression (WIP1) in Childhood Acute Lymphoblastic Leukemia.","authors":"Maryam Zanjirband, Soheila Rahgozar, Narges Aberuyi","doi":"10.20517/cdr.2022.113","DOIUrl":"https://doi.org/10.20517/cdr.2022.113","url":null,"abstract":"<p><p><b>Aim:</b> Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). <b>Methods:</b> miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. <b>Results:</b> MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21<sup>WAF1</sup> and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. <b>Conclusion:</b> This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9828958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yaling Jiang, Valentina Donati, Godefridus J Peters, Elisa Giovannetti, Dong Mei Deng
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam et al. discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.
{"title":"Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance.","authors":"Yaling Jiang, Valentina Donati, Godefridus J Peters, Elisa Giovannetti, Dong Mei Deng","doi":"10.20517/cdr.2023.06","DOIUrl":"https://doi.org/10.20517/cdr.2023.06","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam <i>et al.</i> discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9823119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander M Scherbakov, Anna A Basharina, Danila V Sorokin, Ekaterina I Mikhaevich, Iman E Mizaeva, Alexandra L Mikhaylova, Tatiana A Bogush, Mikhail A Krasil'nikov
Aim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.
{"title":"Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance.","authors":"Alexander M Scherbakov, Anna A Basharina, Danila V Sorokin, Ekaterina I Mikhaevich, Iman E Mizaeva, Alexandra L Mikhaylova, Tatiana A Bogush, Mikhail A Krasil'nikov","doi":"10.20517/cdr.2022.96","DOIUrl":"https://doi.org/10.20517/cdr.2022.96","url":null,"abstract":"<p><p><b>Aim:</b> The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. <b>Methods:</b> The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. <b>Results:</b> The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (<i>P</i> < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC<sub>50</sub> value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (<i>P</i> < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. <b>Conclusion:</b> Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}