Decreased functional activity of multidrug resistance protein in primary colorectal cancer

Abstract

BackgroundThe ATP-Binding Cassette (ABC)-transporter MultiDrug Resistance Protein 1 (MDR1) and Multidrug Resistance Related Protein 1 (MRP1) are expressed on the surface of enterocytes, which has led to the belief that these high capacity transporters are responsible for modulating chemosensitvity of colorectal cancer. Several immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) studies have provided controversial results in regards to the expression levels of these two ABC-transporters in colorectal cancer. Our study was designed to determine the yet uninvestigated functional activity of MDR1 and MRP1 transporters in normal human enterocytes compared to colorectal cancer cells from surgical biopsies.Methods100 colorectal cancer and 28 adjacent healthy mucosa samples were obtained by intraoperative surgical sampling. Activity of MDR1 and MRP1 of viable epithelial and cancer cells were determined separately with the modified calcein-assay for multidrug resistance activity and sufficient data of 73 cancer and 11 healthy mucosa was analyzed statistically.ResultsSignificantly decreased mean MDR1 activity was found in primary colorectal cancer samples compared to normal mucosa, while mean MRP1 activity showed no significant change. Functional activity was not affected by gender, age, stage or grade and localization of the tumor.ConclusionWe found lower MDR activity in cancer cells versus adjacent, apparently, healthy control tissue, thus, contrary to general belief, MDR activity seems not to play a major role in primary drug resistance, but might rather explain preferential/selective activity of Irinotecan and/or Oxaliplatin. Still, this picture might be more complex since chemotherapy by itself might alter MDR activity, and furthermore, today limited data is available about MDR activity of cancer stem cells in colorectal cancers.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1675739129145824

Combination of long-acting TRAIL and tumor cell-targeted photodynamic therapy as a novel strategy to overcome chemotherapeutic multidrug resistance and TRAIL resistance of colorectal cancer

“…However, the chemical efflux pump proteins, i.e. , the ATP-binding cassette (ABC) transporters, are ubiquitously expressed in enterocytes 3 , 4 , making it easier for CRC cells to develop chemotherapeutic multidrug resistance (MDR) for both conventional chemotherapeutics and the novel molecular-targeted chemicals 5 . Owing to the differences in cell entry and action mechanisms, macromolecular proteins such as anti-EGFR monoclonal antibody can bypass the MDR pathway for small chemical drugs.…”

The role of MRP1 in the multidrug resistance of colorectal cancer

“…Recently, Ji et al (9) reported elevated MRP1 expression in CRC tissues, and identified a significant correlation between MRP1 expression and Dukes' stage, in addition to poor patient prognosis. Micsik et al (11) suggested that MDR activity may be associated with acquired chemoresistance in CRC. Furthermore, another study suggested that MRP1 inhibition was involved in the fingolimod-induced chemosensitization of HCT-8/5-FU cells (10).…”

“…Several studies identified no association between MRP1 expression and CRC-associated MDR (5-7). However, other studies identified high expression levels of MRP1 in CRC cells and produced results that indicated that there was a significant correlation between MRP1 expression and tumor stage/poor patient prognosis, in addition to an association with acquired chemoresistance, in CRC (8)(9)(10)(11). The results of a study performed by Xing et al (10) suggest that MRP1 expression is not correlated with the functional changes of MRP1 transporters, which may partially explain the inconsistency in the results of the studies discussed above.…”

MRP1 expression in CTCs confers resistance to irinotecan‐based chemotherapy in metastatic colorectal cancer

“…They found a correlation between the expression of BCRP and MRP1 and clinical outcome in the patients treated with anthracycline‐based chemotherapy. Regarding colorectal cancer, Micsik et al, measured functional activity of MDR1 and MRP1 by modified calcein‐assay in primary colorectal tumors and compared to normal mucosa. They found no difference in MRP1 activity between these sites.…”