Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury.
The inhibition of nuclear factor kappa B (NF-kappaB) by, for instance, curcumin is becoming an important new approach in combination with chemotherapy or irradiation for the treatment of a variety of cancers including haematological malignancies. A dose-limiting side effect of anticancer therapy in the gastrointestinal tract is mucosal barrier injury. It is hypothesised that mucosal barrier injury is initiated and amplified by proinflammatory-and NF-kappaB-regulated mediators. Therefore, the effect of NF-kappaB inhibition was studied in the onset of mucosal barrier injury. In response to cytostatic drug treatment (arabinoside cytosine (Ara-C) and methotrexate (MTX)), NF-kappaB was activated in intestinal epithelial cells (IEC-6) resulting in an NF-kappaB-related induction of tumour necrosis factor alpha and monocyte chemoattractant protein-1. NF-kappaB inhibition increased the susceptibility of IEC-6 cells to Ara-C as well as MTX-induced cell death when obtained by the addition of caffeic acid phenethyl ester (CAPE), but not using curcumin. In an animal model for MTX-induced mucosal barrier injury, the induction of NF-kappaB-related cytokines and chemokines was detected upon treatment with MTX. Despite increased susceptibility shown in vitro, the inhibition of NF-kappaB resulted in a partial amelioration of villous atrophy normally seen in the small intestine upon MTX treatment. These results show that the inhibition of NF-kappaB does not increase intestinal side effects of the anticancer treatment, suggesting a safe use of curcumin and CAPE in combination with anticancer treatment.
van't Land
B
B
Numico-Research, Department of Condition and Disease Specific Research, CA Wageningen, The Netherlands.
Blijlevens
N M A
NM
Marteijn
J
J
Timal
S
S
Donnelly
J P
JP
de Witte
T J M
TJ
M'Rabet
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002109:Caffeic Acids / Q000494:pharmacology; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D016328:NF-kappa B / Q000819:agonists / Q000037:antagonists & inhibitors*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D002109:Caffeic Acids; D016328:NF-kappa B; D003561:Cytarabine; C055494:caffeic acid phenethyl ester; D003474:Curcumin; D010626:Phenylethyl Alcohol; D008727:Methotrexate