Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells
Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs bec...
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| description | Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer. |
| doi_str_mv | 10.1371/journal.pone.0107596 |
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Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0107596</identifier><identifier>PMID: 25264898</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Bioactive compounds ; Biology and Life Sciences ; Biomarkers ; Biomarkers, Tumor - metabolism ; Biophysics ; Breast cancer ; Cancer ; Carboplatin ; Carcinoma, Ovarian Epithelial ; CD34 antigen ; CD44 antigen ; Cell cycle ; Cell Division - drug effects ; Cell Line, Tumor ; Chemotherapy ; Cisplatin ; Cisplatin - administration & dosage ; Cisplatin - pharmacology ; Deoxyribonucleic acid ; DNA ; Drug resistance ; Female ; Gene expression ; Humans ; Lupus ; Medical prognosis ; Medicine and Health Sciences ; Metastases ; Metastasis ; Mice ; Mice, Nude ; Neoplasm Metastasis - prevention & control ; Neoplasms, Glandular and Epithelial - metabolism ; Neoplasms, Glandular and Epithelial - pathology ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Notch1 protein ; Oct-4 protein ; Organs ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - metabolism ; Ovarian Neoplasms - pathology ; Paclitaxel ; Physiology ; Platinum ; Signal transduction ; Signaling ; Stem cell transplantation ; Stem cells ; Surgery ; Tumors ; Withanolides - administration & dosage ; Withanolides - pharmacology ; Womens health</subject><ispartof>PloS one, 2014-09, Vol.9 (9), p.e107596</ispartof><rights>2014 Kakar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Although this regimen is initially effective in a high percentage of cases, unfortunately within few months of initial treatment, tumor relapse occurs because of platinum-resistance. This is attributed to chemo-resistance of cancer stem cells (CSCs). Herein we show for the first time that withaferin A (WFA), a bioactive compound isolated from the plant Withania somnifera, when used alone or in combination with cisplatin (CIS) targets putative CSCs. Treatment of nude mice bearing orthotopic ovarian tumors generated by injecting human ovarian epithelial cancer cell line (A2780) with WFA and cisplatin (WFA) alone or in combination resulted in a 70 to 80% reduction in tumor growth and complete inhibition of metastasis to other organs compared to untreated controls. Histochemical and Western blot analysis of the tumors revealed that inclusion of WFA (2 mg/kg) resulted in a highly significant elimination of cells expressing CSC markers - CD44, CD24, CD34, CD117 and Oct4 and downregulation of Notch1, Hes1 and Hey1 genes. In contrast treatment of mice with CIS alone (6 mg/kg) had opposite effect on those cells. Increase in cells expressing CSC markers and Notch1 signaling pathway in tumors exposed to CIS may explain recurrence of cancer in patients treated with carboplatin and paclitaxel. Since, WFA alone or in combination with CIS eliminates putative CSCs, we conclude that WFA in combination with CIS may present more efficacious therapy for ovarian cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25264898</pmid><doi>10.1371/journal.pone.0107596</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-09, Vol.9 (9), p.e107596 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1566322315 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Bioactive compounds Biology and Life Sciences Biomarkers Biomarkers, Tumor - metabolism Biophysics Breast cancer Cancer Carboplatin Carcinoma, Ovarian Epithelial CD34 antigen CD44 antigen Cell cycle Cell Division - drug effects Cell Line, Tumor Chemotherapy Cisplatin Cisplatin - administration & dosage Cisplatin - pharmacology Deoxyribonucleic acid DNA Drug resistance Female Gene expression Humans Lupus Medical prognosis Medicine and Health Sciences Metastases Metastasis Mice Mice, Nude Neoplasm Metastasis - prevention & control Neoplasms, Glandular and Epithelial - metabolism Neoplasms, Glandular and Epithelial - pathology Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Notch1 protein Oct-4 protein Organs Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - metabolism Ovarian Neoplasms - pathology Paclitaxel Physiology Platinum Signal transduction Signaling Stem cell transplantation Stem cells Surgery Tumors Withanolides - administration & dosage Withanolides - pharmacology Womens health |
| title | Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T18%3A17%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Withaferin%20a%20alone%20and%20in%20combination%20with%20cisplatin%20suppresses%20growth%20and%20metastasis%20of%20ovarian%20cancer%20by%20targeting%20putative%20cancer%20stem%20cells&rft.jtitle=PloS%20one&rft.au=Kakar,%20Sham%20S&rft.date=2014-09-29&rft.volume=9&rft.issue=9&rft.spage=e107596&rft.pages=e107596-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0107596&rft_dat=%3Cproquest_plos_%3E3446924861%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1566322315&rft_id=info:pmid/25264898&rft_doaj_id=oai_doaj_org_article_afd6013e53b746a698c26ded50524679&rfr_iscdi=true |