Journal
CURRENT DRUG TARGETS
Volume 18, Issue 8, Pages 889-900Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1389450116666150223121508
Keywords
Chemotherapy; drug metabolism; drug transport; liver cancer; pharmacology; treatment; tumor
Categories
Funding
- Carlos III Institute of Health, Spain [FIS PI15/00179, PI16/00598]
- Spanish Ministerio de Ciencia e Innovacion [SAF2013-40620-R, SAF2016-75197-R]
- Junta de Castilla y Leon [SA015U13, BIO/SA65/13, BIO/SA52/15]
- Fundacion Mutua Madrilena
- CIBERehd [EHD15PI05/ 2016]
- Fundacion Miguel Casado San Jose
- Junta de Catilla y Leon
- Fondo Social Europeo [EDU/858/2013]
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The multidrug resistance (MDR) phenotype accounts for the poor response of cholangio-carcinoma to available antitumor drugs. This is an important limitation to the use of pharmacological approaches, both as adjuvant therapies and for treating advanced CCA when surgical removal is not possible. MDR is the result of a complex combination of defense mechanisms against toxic compounds already present in cholangiocytes, which play a role in the physiology of these cells by protecting the biliary epithelium from the toxins reaching the biliary tree with the blood that perfuses this tissue, or that are secreted by hepatocytes into bile, to which cholangiocytes are exposed. These mechanisms of chemoresistance (MOC) are also present, usually with enhanced efficacy, in tumors derived from cholangiolar cells. The present review article is an update of the state-of-the-art regarding the MOC involved in the poor response of CCA to antitumor drugs. These MOC have been classified as: changes in the amount of drug in the cells due to decreased uptake (MOC-1a) or enhanced efflux (MOC-1b); altered proportions between prodrug, active drug and inactive metabolites (MOC-2); changes in the molecular targets of antitumor drugs (MOC-3); an enhanced ability of tumor cells to repair drug-induced DNA damage (MOC-4), and an impaired apoptosis/survival balance (MOC-5).
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