Intestine / colon cancer cells

Intestine/colon cancer cells The caco-2 intestinal cell monolayer is a good model for testing permeability and oral deliverability of compounds [39]. 

Breast Cancer Resistance Protein (BCRP, also known as MXR or ABCP), first cloned from mitoxantrone and anthracycline-resistant breast and colon cancer cells [188, 189] is a half-transporter efflux pump believed to function as a homo-or hetero-dimer. Following its identification, BCRP-mediated drug resistance was observed for topoisomerase inhibitors including camptothecins [190, 191] and in-dolocarbazoles [192]. In normal tissues, BCRP was detected in placental syncytio-trophoblasts, hepatocyte canalicular membrane, apical intestinal epithelia and vascular endothelial cells [193]. These findings support the important role BCRP plays in modulating topotecan bioavailability, fetal exposure and hepatic elimination [194]. Considering that the substrates and tissue distributions for BCRP overlap somewhat with MDR1 and MRPs [195], additional studies will be required to define the relative contribution of each of these transporters in the overall and tis-... 

Thompson PD, Jurutka PW, Whitfield GK, et al. Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements. Biochem Biophys Res Commun 2002 299(5) 730-738. 

Bile acids that escape enterohepatic circulation and pass to the colon can be cytotoxic to colonocytes. Damaged cells undergo apoptosis and are shed into the lumen. To maintain cell homeostasis, new cells must be produced. This replacement can result in an increase in cell proliferation rate that can increase the risk of mutations in tumor-related genes and lead to carcinoma development. Moschetta et al. (2000) showed that sphingomyelin protected against bile acid-induced cytotoxicity in human CaCo-2 colon cancer cells, a common model for studying intestinal cell function. 

A supplementation of procyanidins from cocoa significantly decreased plasma or liver cholesterol and triglycerides in rats fed a high cholesterol diet. The capacity of procyanidins to inhibit intestinal absorption of cholesterol appeared to be one of the mechanisms (Osakabe and Yamagishi, 2009). Cocoa procyanidins had sustained benefits to reverse vascular dysfunction in diabetic patients (Balzer et ah, 2008). Such benefits had been attributed to (—)-epicatechin, which is the constituent unit of cocoa procyanidins (Schroeter et ah, 2006). Procyanidins from cacao were found to inhibit growth of human breast cancer and colonic cancer cells (Camesecchi et ah, 2002 Ramljak et ah, 2005). 

Another human colonic cancer cell line is T84, which forms monolayers that are even tighter than those of the Caco-2. It has been described as resembling a colonic crypt cell phenotype. Hence, these cells have been used mainly in studies of epithelial ion secretion and are generally not considered to be adequate for drug transport studies, particularly with respect to carrier-mediated processes [13, 91, 92]. The rat intestinal epithelial cell line IEC-18 has been evaluated as a model to study small intestinal epithelial permeability. This cell line, which forms very leaky monolayers, was proposed to be a better model than the Caco-2 monolayers for evaluating the small intestinal paracellular permeation of hydrophilic molecules [93]. Importantly, the leaky tight junctions of the IEC-18 cells are a result of an undeveloped paracellular barrier lacking the perijunctional actin belt. In addition, the IEC-18 cells have minute expression of transporters [91, 93]. 

Tran, C.P., FamUari, M., Parker, L.M. et al. (1998) Short-chain fatty acids inhibit intestinal trefoil factor gene expression in colon cancer cells. Am. J. Physiol Gastrointest. Liver Physiol, 275, G85-G94. 

The risk of colon cancer appears to be inversely related to calcium and folate intake. Calciums protective effect may be related to a reduction in mucosal cell proliferation rates or through its binding to bile salts in the intestine, whereas dietary folate helps in maintaining normal bowel mucosa. Additional micronutrient deficiencies have been demonstrated through several studies to increase colorectal cancer risk and include selenium, vitamin C, vitamin D, vitamin E, and 3-carotene however, the benefit of dietary supplementation does not appear to be substantial.11... 

In contrast to P-gp and the MRP proteins, the breast cancer resistance protein (BCRP) contains six transmembrane domains and only one ATP-binding domain. It was first cloned from the breast cancer cell line MCF-7 selected in doxombicin, in the presence of the P-gp inhibitor verapamil. It is found in many human tissues, such as the placenta, small intestine, colon, and liver [133], It is localized to the apical membrane of epithelial cells of the small intestine and colon and to the bile canalicular membrane in the liver and is involved in reducing intestinal uptake, increasing hepatobiliary excretion, etc., leading to diminished oral bioavailability. cDNA sequences identical to BCRP and named MXR and ABCP, respectively, were independently isolated from human colon carcinoma cells and human placenta [134], BCRP requires... 

In addition to the treatment of pain and inflammation, COX-2 inhibitors might be of benefit in other indications. Expression of COX-2 in colon cancer, intestinal adenomas, and other cancer cells as well as clinical studies with COX-2 inhibitors, suggest the use of COX-2 inhibitors in cancer (Masferrer et al., 1999). Expression of COX-2 in angiogenesis follows the same route since angiogenesis is important for blood supply and hence the growth of many tumors. 

Additionally, patients with familial adenomatous polyposis, an autosomal-dominant disease characterized by numerous small intestinal and colonic polyps with a nearly universal progression to colon cancer, have a favorable response to NSAIDs. Administration of NSAID (usually sulindac) to patients with this disorder reduces the number and size of polyps (DuBois et al., 1996). Recent biochemical evidence indicates that colon polyps and colon cancer are frequendy associated with induction of Cox-2 in the lesion as assessed by expression of Cox-2 mRNA and protein. Such induction appears to correlate with growth of the lesion, and inhibition of Cox-2 correlates with apoptosis of the involved cells (Gupta and DuBois, 1998). 

In recent years, it has been found that the barrier function of the intestinal epithelium cannot be adequately described by a combination of metabolic and physical barriers alone. Apically polarized efflux systems are known to be present in cancer cells and represent a major barrier to the uptake of a wide variety of chemotherapeutic agents (i.e. in multi-drag resistance). Efflux systems have also now been identified in normal intestinal and colonic cells, and also at other epithelial sites. 

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