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.
| Original language | English |
|---|---|
| Pages (from-to) | 975-984 |
| Number of pages | 10 |
| Journal | Current Drug Metabolism |
| Volume | 12 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Dec 2011 |
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Keywords
- Colorectal cancer
- Drug resistance
- Folate status
- Preclinical and clinical studies
ASJC Scopus subject areas
- Pharmacology
- Clinical Biochemistry
Cite this
The impact of folate status on the efficacy of colorectal cancer treatment. / Porcelli, Letizia; Assaraf, Yehuda G.; Azzariti, Amalia; Paradiso, Angelo; Jansen, Gerrit; Peters, Godefridus J.
In: Current Drug Metabolism, Vol. 12, No. 10, 12.2011, p. 975-984.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The impact of folate status on the efficacy of colorectal cancer treatment
AU - Porcelli, Letizia
AU - Assaraf, Yehuda G.
AU - Azzariti, Amalia
AU - Paradiso, Angelo
AU - Jansen, Gerrit
AU - Peters, Godefridus J.
PY - 2011/12
Y1 - 2011/12
N2 - 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.
AB - 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.
KW - Colorectal cancer
KW - Drug resistance
KW - Folate status
KW - Preclinical and clinical studies
UR - http://www.scopus.com/inward/record.url?scp=82355170123&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=82355170123&partnerID=8YFLogxK
U2 - 10.2174/138920011798062274
DO - 10.2174/138920011798062274
M3 - Article
C2 - 21787267
AN - SCOPUS:82355170123
VL - 12
SP - 975
EP - 984
JO - Current Drug Metabolism
JF - Current Drug Metabolism
SN - 1389-2002
IS - 10
ER -