Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues
More than 40 years ago, the observation that doxorubicin-resistant tumor cells were cross-resistant to several structurally different anticancer agents was the first step in the discovery of P-glycoprotein (P-gp). P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters;its overexp...
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Frontiers Media SA
2021
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| _version_ | 1869524077697302528 |
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| author | Chiara Riganti Enrico Mini Stefania Nobili |
| author_browse | Chiara Riganti Enrico Mini Stefania Nobili |
| author_facet | Chiara Riganti Enrico Mini Stefania Nobili |
| author_sort | Chiara Riganti |
| collection | Directory of Open Access Books |
| description | More than 40 years ago, the observation that doxorubicin-resistant tumor cells were cross-resistant to several structurally different anticancer agents was the first step in the discovery of P-glycoprotein (P-gp). P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters;its overexpression has become a therapeutic target for overcoming multidrug resistance in tumors. However, P-gp is also expressed in cells of normal tissues where it plays a physiological role, by protecting them from the toxic effects of xenobiotics. Also, ABCB1 gene polymorphisms may influence the response to anticancer drugs substrate of P-gp. Several strategies to overcome P-gp tumor drug resistance have been suggested. P-gp 'circumvention’ is the most explored and is based on the coadministration of anticancer agents and pump inhibitors (P-gp modulators). Despite the positive findings obtained in preclinical studies, results of clinical trials are not yet successful and clinical research is still ongoing. Other investigational approaches have been studied (e.g. P-gp targeting antibodies, use of antisense strategies or transcriptional regulators targeting ABCB1 gene expression) but their use is still circumscribed to the preclinical setting. A further approach is represented by the encapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles. This strategy has shown higher efficacy in tumor previously treated with the free drug. The reasons explaining the increased efficacy of liposomal/nanoparticle-based drugs in Pgp-overexpressing tumors include the coating with specific surfactants, the composition changes in the plasma membrane microdomains where P-gp is embedded, the direct impairment of P-gp catalytic mechanisms exerted by specific component of the liposomal shell, but are not yet fully understood. A second strategy to overcome P-gp tumor drug resistance is represented by exploiting the P-gp presence. Actually, P-gp-overexpressing cells show increased sensitivity (collateral sensitivity) to some drugs (e.g. verapamil, narcotic analgesics) and to some investigational compounds (e.g. NSC73306). P-gp-overexpressing cell are hypersensitive to reactive oxygen species, to agents perturbing the energetic metabolic pathways, changing the membrane compositions, reducing the efflux of endogenous toxic catabolites. However, the mechanisms explaining collateral sensitivity have not been fully elucidated. Another approach to exploit P-gp is represented by ABCB1 gene transfer to transform bone marrow progenitor cells into a drug resistant state which may allow conventional or higher doses of anticancer drug substrates of P-gp to be administered safely after transplantation. More recently the development and introduction in the clinics of anticancer drugs which are not substrates of P-gp (e.g. new microtubule modulators, topoisomerase inhibitors) has provided a new and promising strategy to overcome P-gp tumor drug resistance (P-gp 'evasion'). This ‘research topic’ issue aims at exploding the above mentioned matters, in particular by: -retracing the history of the first researches on P-gp - describing the physiological role of P-gp - describing the molecular basis, structural features and mechanism of action of P-gp - describing diagnostic laboratory methods useful to determine the expression of P-gp and its transporter function - describing strategies to overcome tumor drug resistance due to P-gp and other ABC transporters - indicating novel approaches to overcome P-gp multidrug resistance, ranging from basic research studies to pre-clinical/clinical studies. |
| format | Online |
| id | doab-20.500.12854ir-54062 |
| institution | Directory of Open Access Books |
| language | eng |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Frontiers Media SA |
| publisherStr | Frontiers Media SA |
| record_format | ojs |
| spelling | doab-20.500.12854ir-540622024-03-31T13:10:27Z Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues Chiara Riganti Enrico Mini Stefania Nobili R5-920 RM1-950 RC254-282 Q1-390 multidrug resistance reversing strategies P-Glycoprotein Cancer thema EDItEUR::M Medicine and Nursing More than 40 years ago, the observation that doxorubicin-resistant tumor cells were cross-resistant to several structurally different anticancer agents was the first step in the discovery of P-glycoprotein (P-gp). P-gp belongs to the superfamily of ATP-binding cassette (ABC) transporters;its overexpression has become a therapeutic target for overcoming multidrug resistance in tumors. However, P-gp is also expressed in cells of normal tissues where it plays a physiological role, by protecting them from the toxic effects of xenobiotics. Also, ABCB1 gene polymorphisms may influence the response to anticancer drugs substrate of P-gp. Several strategies to overcome P-gp tumor drug resistance have been suggested. P-gp 'circumvention’ is the most explored and is based on the coadministration of anticancer agents and pump inhibitors (P-gp modulators). Despite the positive findings obtained in preclinical studies, results of clinical trials are not yet successful and clinical research is still ongoing. Other investigational approaches have been studied (e.g. P-gp targeting antibodies, use of antisense strategies or transcriptional regulators targeting ABCB1 gene expression) but their use is still circumscribed to the preclinical setting. A further approach is represented by the encapsulation of P-gp substrate anticancer drugs into liposomes or nanoparticles. This strategy has shown higher efficacy in tumor previously treated with the free drug. The reasons explaining the increased efficacy of liposomal/nanoparticle-based drugs in Pgp-overexpressing tumors include the coating with specific surfactants, the composition changes in the plasma membrane microdomains where P-gp is embedded, the direct impairment of P-gp catalytic mechanisms exerted by specific component of the liposomal shell, but are not yet fully understood. A second strategy to overcome P-gp tumor drug resistance is represented by exploiting the P-gp presence. Actually, P-gp-overexpressing cells show increased sensitivity (collateral sensitivity) to some drugs (e.g. verapamil, narcotic analgesics) and to some investigational compounds (e.g. NSC73306). P-gp-overexpressing cell are hypersensitive to reactive oxygen species, to agents perturbing the energetic metabolic pathways, changing the membrane compositions, reducing the efflux of endogenous toxic catabolites. However, the mechanisms explaining collateral sensitivity have not been fully elucidated. Another approach to exploit P-gp is represented by ABCB1 gene transfer to transform bone marrow progenitor cells into a drug resistant state which may allow conventional or higher doses of anticancer drug substrates of P-gp to be administered safely after transplantation. More recently the development and introduction in the clinics of anticancer drugs which are not substrates of P-gp (e.g. new microtubule modulators, topoisomerase inhibitors) has provided a new and promising strategy to overcome P-gp tumor drug resistance (P-gp 'evasion'). This ‘research topic’ issue aims at exploding the above mentioned matters, in particular by: -retracing the history of the first researches on P-gp - describing the physiological role of P-gp - describing the molecular basis, structural features and mechanism of action of P-gp - describing diagnostic laboratory methods useful to determine the expression of P-gp and its transporter function - describing strategies to overcome tumor drug resistance due to P-gp and other ABC transporters - indicating novel approaches to overcome P-gp multidrug resistance, ranging from basic research studies to pre-clinical/clinical studies. 2021-02-11T20:19:00Z 2021-02-11T20:19:00Z 2016-08-16 10:34:25 2015 book 19523 16648714 9782889196159 https://directory.doabooks.org/handle/20.500.12854/54062 eng Frontiers Research Topics image/jpeg Attribution 4.0 International http://www.frontiersin.org/books/Multidrug_resistance_in_Cancer_Pharmacological_Strategies_from_Basic_Research_to_Clinical_Issues/614 http://journal.frontiersin.org/researchtopic/1154/multidrug-resistance-in-cancer-pharmacological-strategies-from-basic-research-to-clinical-issues Frontiers Media SA 10.3389/978-2-88919-615-9 10.3389/978-2-88919-615-9 bf5ce210-e72e-4860-ba9b-c305640ff3ae 9782889196159 99 open access |
| spellingShingle | R5-920 RM1-950 RC254-282 Q1-390 multidrug resistance reversing strategies P-Glycoprotein Cancer thema EDItEUR::M Medicine and Nursing Chiara Riganti Enrico Mini Stefania Nobili Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues |
| title | Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues |
| title_full | Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues |
| title_fullStr | Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues |
| title_full_unstemmed | Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues |
| title_short | Multidrug resistance in Cancer: Pharmacological Strategies from Basic Research to Clinical Issues |
| title_sort | multidrug resistance in cancer pharmacological strategies from basic research to clinical issues |
| topic | R5-920 RM1-950 RC254-282 Q1-390 multidrug resistance reversing strategies P-Glycoprotein Cancer thema EDItEUR::M Medicine and Nursing |
| topic_facet | R5-920 RM1-950 RC254-282 Q1-390 multidrug resistance reversing strategies P-Glycoprotein Cancer thema EDItEUR::M Medicine and Nursing |
| url | 19523 |
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