Role of curcumin and the inhibition of NF-κB in the onset of chemotherapy-induced mucosal barrier injury

Abstract

The inhibition of nuclear factor kappa B (NF-jB) 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-jB-regulated mediators. Therefore, the effect of NF-jB inhibition was studied in the onset of mucosal barrier injury. In response to cytostatic drug treatment (arabinoside cytosine (Ara-C) and methotrexate (MTX)), NF-jB was activated in intestinal epithelial cells (IEC-6) resulting in an NF-jB-related induction of tumour necrosis factor alpha and monocyte chemoattractant protein-1. NF-jB 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-jB-related cytokines and chemokines was detected upon treatment with MTX. Despite increased susceptibility shown in vitro, the inhibition of NF-jB 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-jB does not increase intestinal side effects of the anticancer treatment, suggesting a safe use of curcumin and CAPE in combination with anticancer treatment.

Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients

“…1 It begins immediately after starting anticancer therapy with the activation of the nuclear transcription factor NF-kB resulting in the production and release of proinflammatory cytokines by various cells including lymphocytes, macrophages, endothelial cells and gut epithelial cells. 2,3 Gut epithelial cells produce not only proinflammatory cytokines like TNF-a, interleukin (IL)-1a and IL-6, but also the chemokines, monocyte chemoattractant protein-1 (MCP-1) and IL-8, antimicrobial peptides (defensins, cathelicidins, lactoferrin) and the acute phase protein, LPS-binding protein (LBP). [3][4][5] The release of proinflammatory cytokines and the blocking of clonogenic epithelial stem cell renewal results in apoptosis and necrosis, which manifests itself as epithelial atrophy and ulcerative lesions.…”

“…2,3 Gut epithelial cells produce not only proinflammatory cytokines like TNF-a, interleukin (IL)-1a and IL-6, but also the chemokines, monocyte chemoattractant protein-1 (MCP-1) and IL-8, antimicrobial peptides (defensins, cathelicidins, lactoferrin) and the acute phase protein, LPS-binding protein (LBP). [3][4][5] The release of proinflammatory cytokines and the blocking of clonogenic epithelial stem cell renewal results in apoptosis and necrosis, which manifests itself as epithelial atrophy and ulcerative lesions. 6 The latter are a potential portal of entry for oral viridans (alpha-haemolytic) streptococci (OVS), which are universal commensals of the oral cavity placing haematopoietic stem cell transplant (HSCT) recipients at risk of developing bacteraemia due to these bacteria.…”

Antimicrobials, mucosal coating agents, anesthetics, analgesics, and nutritional supplements for alimentary tract mucositis

“…Two recent publications described the effect of curcumin on chemotherapy-and radiation-induced mucositis in animal models [24,25]. Both studies reported significant reduction in incidence and severity of mucositis in curcumin pre-treated animals.…”

Codelivery of curcumin and doxorubicin by MPEG-PCL results in improved efficacy of systemically administered chemotherapy in mice with lung cancer

“…11 Both reactive oxygen species and activation of the c-Jun NH2-terminal kinase pathway are crucial elements in the success of chemotherapy. 7 Curcumin may inhibit tumor growth via multiple mechanisms, including antitumor angiogenesis, 12,13 suppression of proliferation, 14,15 induction of apoptosis, 8,16 and prevention of metastasis. 17,18 However, the clinical applications of curcumin remain limited because of its short biological half-life, poor solubility resulting in poor absorption, and low bioavailability via the oral route.…”

“…There is some evidence suggesting that curcumin is an ideal chemosensitizer for chemotherapy and that it helps to protect patients from the side effects of treatment. [5][6][7][8][9][10] Curcumin is a highly effective scavenger of reactive oxygen species and also inhibits the c-Jun NH2-terminal kinase pathway. 11 Both reactive oxygen species and activation of the c-Jun NH2-terminal kinase pathway are crucial elements in the success of chemotherapy.…”