The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance.

Chemotherapy in cancer patients is still not satisfactory because of drug resistance. The main mechanism of drug resistance results from the ability of cancer cells to actively expel therapeutic agents via transport proteins of the ABC family. ABCB1 and ABCG2 are the two main proteins responsible for drug resistance in cancers. Recent investigations indicate that aldehyde dehydrogenase (ALDH) can also be involved in drug resistance. Expression of the ABC transporters and ALDH enzymes is observed in normal stem cells, cancer stem cells and drug resistant cancers. Current chemotherapy regimens remove the bulk of the tumour but are usually not effective against cancer stem cells (CSCs) expressing ALDH. As a result, the number of ALDH positive drug resistant CSCs increases after chemotherapy. This indicates that therapies targeting drug resistant CSCs should be developed. A number of therapies targeting CSCs are currently under investigation. These therapies include differentiation therapy using different retinoic acids (RA) as simple agents or in combination with DNA methyltransferase inhibitors (DNMTi) and/or histone deacetylase inhibitors (HDACi). Therapies that target cancer stem cell signaling pathways are also under investigation. A number of natural compounds are effective against cancer stem cells and lead to decreasing numbers of ALDH positive cells and downregulation of the ABC proteins. Combinations of differentiation therapies or therapies targeting CSC signaling pathways with classical cytostatics seem promising. This review discusses the role of ALDH and ABC proteins in the development of drug resistance in cancer and current therapies designed to target CSCs.