Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer
Repetitive, low-dose (metronomic; METRO) drug administration of some anticancer agents can overcome drug resistance and increase drug efficacy in many cancers, but the mechanisms are not understood fully. Previously, we showed that METRO dosing of topotecan (TOPO) is more effective than conventional...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.736951/full |
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| author | Taraswi Mitra Ghosh Jason White Joshua Davis Suman Mazumder Suman Mazumder Teeratas Kansom Elena Skarupa Grafton S. Barnett Gary A. Piazza R. Curtis Bird Amit K. Mitra Amit K. Mitra Amit K. Mitra Clayton Yates Clayton Yates Clayton Yates Brian S. Cummings Robert D. Arnold Robert D. Arnold Robert D. Arnold |
| author_facet | Taraswi Mitra Ghosh Jason White Joshua Davis Suman Mazumder Suman Mazumder Teeratas Kansom Elena Skarupa Grafton S. Barnett Gary A. Piazza R. Curtis Bird Amit K. Mitra Amit K. Mitra Amit K. Mitra Clayton Yates Clayton Yates Clayton Yates Brian S. Cummings Robert D. Arnold Robert D. Arnold Robert D. Arnold |
| author_sort | Taraswi Mitra Ghosh |
| collection | DOAJ |
| description | Repetitive, low-dose (metronomic; METRO) drug administration of some anticancer agents can overcome drug resistance and increase drug efficacy in many cancers, but the mechanisms are not understood fully. Previously, we showed that METRO dosing of topotecan (TOPO) is more effective than conventional (CONV) dosing in aggressive human prostate cancer (PCa) cell lines and in mouse tumor xenograft models. To gain mechanistic insights into METRO-TOPO activity, in this study we determined the effect of METRO- and CONV-TOPO treatment in a panel of human PCa cell lines representing castration-sensitive/resistant, androgen receptor (+/−), and those of different ethnicity on cell growth and gene expression. Differentially expressed genes (DEGs) were identified for METRO-TOPO therapy and compared to a PCa patient cohort and The Cancer Genome Atlas (TCGA) database. The top five DEGs were SERPINB5, CDKN1A, TNF, FOS, and ANGPT1. Ingenuity Pathway Analysis predicted several upstream regulators and identified top molecular networks associated with METRO dosing, including tumor suppression, anti-proliferation, angiogenesis, invasion, metastasis, and inflammation. Further, the top DEGs were associated with increase survival of PCa patients (TCGA database), as well as ethnic differences in gene expression patterns in patients and cell lines representing African Americans (AA) and European Americans (EA). Thus, we have identified candidate pharmacogenomic biomarkers and novel pathways associated with METRO-TOPO therapy that will serve as a foundation for further investigation and validation of METRO-TOPO as a novel treatment option for prostate cancers. |
| first_indexed | 2024-12-23T03:15:20Z |
| format | Article |
| id | doaj.art-78bf5631e26f44058e9dd33c413cb9f1 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-23T03:15:20Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-78bf5631e26f44058e9dd33c413cb9f12022-12-21T18:02:07ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-12-011210.3389/fphar.2021.736951736951Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate CancerTaraswi Mitra Ghosh0Jason White1Joshua Davis2Suman Mazumder3Suman Mazumder4Teeratas Kansom5Elena Skarupa6Grafton S. Barnett7Gary A. Piazza8R. Curtis Bird9Amit K. Mitra10Amit K. Mitra11Amit K. Mitra12Clayton Yates13Clayton Yates14Clayton Yates15Brian S. Cummings16Robert D. Arnold17Robert D. Arnold18Robert D. Arnold19Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesCenter for Pharmacogenomics and Single-Cell Omics, Auburn University, Auburn, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesCenter for Pharmacogenomics and Single-Cell Omics, Auburn University, Auburn, AL, United StatesUAB O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL, United StatesUAB O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesDepartment of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, United StatesDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United StatesDepartment of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United StatesUAB O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, United StatesRepetitive, low-dose (metronomic; METRO) drug administration of some anticancer agents can overcome drug resistance and increase drug efficacy in many cancers, but the mechanisms are not understood fully. Previously, we showed that METRO dosing of topotecan (TOPO) is more effective than conventional (CONV) dosing in aggressive human prostate cancer (PCa) cell lines and in mouse tumor xenograft models. To gain mechanistic insights into METRO-TOPO activity, in this study we determined the effect of METRO- and CONV-TOPO treatment in a panel of human PCa cell lines representing castration-sensitive/resistant, androgen receptor (+/−), and those of different ethnicity on cell growth and gene expression. Differentially expressed genes (DEGs) were identified for METRO-TOPO therapy and compared to a PCa patient cohort and The Cancer Genome Atlas (TCGA) database. The top five DEGs were SERPINB5, CDKN1A, TNF, FOS, and ANGPT1. Ingenuity Pathway Analysis predicted several upstream regulators and identified top molecular networks associated with METRO dosing, including tumor suppression, anti-proliferation, angiogenesis, invasion, metastasis, and inflammation. Further, the top DEGs were associated with increase survival of PCa patients (TCGA database), as well as ethnic differences in gene expression patterns in patients and cell lines representing African Americans (AA) and European Americans (EA). Thus, we have identified candidate pharmacogenomic biomarkers and novel pathways associated with METRO-TOPO therapy that will serve as a foundation for further investigation and validation of METRO-TOPO as a novel treatment option for prostate cancers.https://www.frontiersin.org/articles/10.3389/fphar.2021.736951/fulltopotecanmetronomicprostate cancermCRPCtranscriptomicsRNA sequencing |
| spellingShingle | Taraswi Mitra Ghosh Jason White Joshua Davis Suman Mazumder Suman Mazumder Teeratas Kansom Elena Skarupa Grafton S. Barnett Gary A. Piazza R. Curtis Bird Amit K. Mitra Amit K. Mitra Amit K. Mitra Clayton Yates Clayton Yates Clayton Yates Brian S. Cummings Robert D. Arnold Robert D. Arnold Robert D. Arnold Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer Frontiers in Pharmacology topotecan metronomic prostate cancer mCRPC transcriptomics RNA sequencing |
| title | Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer |
| title_full | Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer |
| title_fullStr | Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer |
| title_full_unstemmed | Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer |
| title_short | Identification and Characterization of Key Differentially Expressed Genes Associated With Metronomic Dosing of Topotecan in Human Prostate Cancer |
| title_sort | identification and characterization of key differentially expressed genes associated with metronomic dosing of topotecan in human prostate cancer |
| topic | topotecan metronomic prostate cancer mCRPC transcriptomics RNA sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.736951/full |
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