title: The impact of folate status on the efficacy of colorectal cancer treatment.
abstract: Over the past three decades, numerous reports have addressed several aspects of drug resistance phenomena. However, little is known regarding the impact that dietary components and nutritional supplements have on the mechanisms of resistance that malignant cells develop to chemotherapeutic agents. The increased fortification of cereals, grains and bread with folic acid (FA) has resulted in a marked rise in folate levels in blood and tissues. Vitamin fortification that includes FA is rather commonly used by cancer patients, but FA is also used to protect against pemetrexed induced side effects in the treatment of non-small cell lung cancer and mesothelioma or that of the antifolate methotrexate in rheumatoid arthritis. Moreover, the reduced folate leucovorin (LV, 5-formyltetrahydrofolate) is also used along with 5-fluorouracil in the treatment of colorectal cancer. Likewise, LV is used to reduce toxicity of methotrexate in the treatment of leukemia. FA can also increase efficacy of unrelated regimens, containing cisplatin. Hence there is growing evidence that dietary supplements as folic acid, can mimic, intensify, or attenuate the effects of unrelated chemotherapeutic agents. The aim of this review is to highlight some new insights in the cellular and molecular mechanisms affected by folate status, leading to chemotherapy resistance, especially towards antifolates in colorectal cancer treatment. This encompasses the effect of folate status on drug export, as well as on the increased expression of mutated target enzymes involved in folate metabolism and on the augmentation of cellular folate pools that impair polyglutamylation of antifolates, ultimately affecting treatment efficacy.
authors.affiliation: Clinical Experimental Oncology Laboratory, National Cancer Institute Giovanni Paolo II, Viale Orazio Flacco, 65, 70124 Bari, Italy. porcelli.letizia@gmail.com
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Yehuda G
authors.initials: YG
authors.lastname: Assaraf
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Gerrit
authors.initials: G
authors.lastname: Jansen
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005492:Folic Acid / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D007408:Intestinal Absorption; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)