Liver and gastrointestinal cancers

Abstract One important limitation in the treatment of liver and gastrointestinal cancers is their poor response to available chemotherapy, which is due in part to efficient mechanisms of defense against antitumor drugs. An important role in chemoresistance is played by ATP-binding cassette (ABC) proteins, normally involved in barrier/secretory functions of the digestive apparatus. ABC pumps, often up-regulated in cancers derived from these organs, actively export antitumor agents from cancer cells, thereby reducing the pharmacological effect of these drugs. Among the ABC proteins with the highest impact on the multidrug resistance (MDR) phenotype of many cancer types is MDR1 or P-glycoprotein (P-gp). This is followed by several members of the ABCC family of multidrug resistance-associated proteins (MRP1, MRP2, MRP3, MRP4, and MRP5) and the breast cancer resistance protein (BCRP). Here we will comment on the role of these ABC proteins in the chemoresistance of clinically relevant types of liver, stomach, pancreas and colon cancer, as well as the results obtained by using synthetic, semisynthetic and natural products as agents to enhance their sensitivity to antitumor drugs, either by inhibiting the activity or reducing the expression of ABC pumps. The development of novel and rapidly advancing technologies, such as nanomedicine and gene manipulation, offer a new broad field of experimentation. To improve the response of liver and gastrointestinal cancers to available antitumor drugs, further investigation should be based on the acquired knowledge regarding the molecular bases of chemoresistance, as well as on the failures and successful results obtained with previously assayed chemosensitizers.