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Understanding how tumor cells overcome chemotherapy-induced cell death is central to improving survival. This brief review summarizes methods to obtain chemoresistant cell lines and details key defenses, including altered drug influx/efflux, metabolic neutralization, DNA repair, apoptosis inhibition, and roles for p53 and ROS levels. It further reviews targeting cancer stem cells.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-brief-review-on-chemoresistance-targeting-cancer-stem-cells-as-an-alternative-approach/378690/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-brief-review-on-chemoresistance-targeting-cancer-stem-cells-as-an-alternative-approach/378690.png","ImageObject",300,407,{"name":92,"@type":93},"Logic","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is chemoresistance a major challenge in cancer treatment?","Question",{"text":112,"@type":113},"Multidrug resistance undermines clinical outcomes and contributes to treatment failure and poor prognosis, including chemoresistant metastatic relapse.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What defense mechanisms do tumor cells use against chemotherapy?",{"text":117,"@type":113},"Tumor cells can alter drug influx/efflux, enhance metabolic neutralization, improve DNA repair, inhibit apoptosis-related cell death, and involve p53 and reactive oxygen species (ROS) levels.",{"name":119,"@type":110,"acceptedAnswer":120},"How do cancer stem cells contribute to chemoresistance and why target them?",{"text":121,"@type":113},"Cancer stem cells persist after chemotherapy and can increase resistance via processes such as EMT, enhanced DNA repair, and avoiding apoptosis through BCL2-family proteins. New approaches aim to decrease cancer stem cell populations, though long-term control is still needed.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},378690,1790332758,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099513958762,"https://ap-avatar.wpscdn.com/avatar/1000023916a998db790?x-image-process=image/resize,m_fixed,w_180,h_180&k=1784791008015729253","Review  \nA Brief Review on Chemoresistance; Targeting Cancer Stem Cells as an Alternative Approach  \nBel²n Toledo 1,†, Aitor Gonz¡lez-Titos 1,†, Pablo Hern¡ndez-Camarero 1,* and Macarena Per¡n 1,2,3, *  \nCitation: Toledo, B.; González-Titos, A.; Hernández-Camarero, P.; Perán, M. A Brief Review on Chemoresistance; Targeting Cancer Stem Cells as an Alternative Approach. Int. J. Mol. Sci. 2023, 24, 4487. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24054487  \nAcademic Editors: Jean Christopher Chamcheu and Jean Fotie  \nReceived: 6 February 2023  \nRevised: 20 February 2023  \nAccepted: 21 February 2023  \nPublished: 24 February 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Department of Health Sciences, University of Ja²n, Campus de las Lagunillas, 23071 Jaen, Spain  \n2 Excellence Research Unit “Modeling Nature”(MNat), University of Granada, 18016 Granada, Spain  \n3 Biopathology and Regenerative Medicine, Institute (IBIMER), University of Granada, Centre for Biomedical Research (CIBM), 18071 Granada, Spain  \n* Correspondence: phc00006@red.ujaen.es (P.H.-C.); mperan@ujaen.es (M.P.)† These authors contributed equally to this work.  \nAbstract: The acquisition of resistance to traditional chemotherapy and the chemoresistant metastatic relapse of minimal residual disease both play a key role in the treatment failure and poor prognosis of cancer. Understanding how cancer cells overcome chemotherapy-induced cell death is critical to improve patient survival rate. Here, we briefly describe the technical approach directed at obtaining chemoresistant cell lines and we will focus on the main defense mechanisms against common chemotherapy triggers by tumor cells. Such as, the alteration of drug influx/efflux, the enhancement of drug metabolic neutralization, the improvement of DNA-repair mechanisms, the inhibition of apoptosis-related cell death, and the role of p53 and reactive oxygen species (ROS) levels in chemoresistance. Furthermore, we will focus on cancer stem cells (CSCs), the cell population that subsists after chemotherapy, increasing drug resistance by different processes such as epithelial-mesenchymal transition (EMT), an enhanced DNA repair machinery, and the capacity to avoid apoptosis mediated by BCL2 family proteins, such as BCL-XL, and the flexibility of their metabolism. Finally, we will review the latest approaches aimed at decreasing CSCs. Nevertheless, the development of long-term therapies to manage and control CSCs populations within the tumors is still necessary.  \nKeywords: chemoresistance; DNA-damaging drugs; cancer stem cells; drug metabolism; p53; reactive oxygen species; drugs pumps; DNA repair; differentiation therapy  \n1. Introduction  \nCurrently, chemotherapy is still considered an irreplaceable front-line therapeutic strategy to combat almost all types of cancers, but multidrug resistance represents a common hurdle that deeply compromises clinical outcomes. Therefore, it is key to identify new resistance biomarkers and to analyze their predictive potential in order to guide treatment regimens [1] . Furthermore, a better understanding of the underlying drug tolerance mechanisms may be critical in achieving alternative therapies to improve oncological patients' prognosis. However, it is challenging since a high heterogeneity of chemoresistance markers expression profiles has been observed between different tumors and even between different cell lines of the same tumor type [2] . In this regard, the development of drug-resistant cell lines is essential to study chemoresistance mechanisms. Figure 1 summarizes the procedure to obtain in vitro chemoresistant cell lin","cbCaidzVfb3VoF0x","https://ap.wps.com/l/cbCaidzVfb3VoF0x","pdf",2141471,18,"English","# Introduction\n## Developing in vitro chemoresistant cell lines\n## Key defense mechanisms in chemoresistance\n## Cancer stem cells and alternative therapeutic approaches","[{\"question\":\"Why is chemoresistance a major challenge in cancer treatment?\",\"answer\":\"Multidrug resistance undermines clinical outcomes and contributes to treatment failure and poor prognosis, including chemoresistant metastatic relapse.\"},{\"question\":\"What defense mechanisms do tumor cells use against chemotherapy?\",\"answer\":\"Tumor cells can alter drug influx/efflux, enhance metabolic neutralization, improve DNA repair, inhibit apoptosis-related cell death, and involve p53 and reactive oxygen species (ROS) levels.\"},{\"question\":\"How do cancer stem cells contribute to chemoresistance and why target them?\",\"answer\":\"Cancer stem cells persist after chemotherapy and can increase resistance via processes such as EMT, enhanced DNA repair, and avoiding apoptosis through BCL2-family proteins. New approaches aim to decrease cancer stem cell populations, though long-term control is still needed.\"}]","A Brief Review on Chemoresistance; Targeting Cancer Stem Cells as an Alternative Approach | PDF",1790231983,45]