The platinum (Pt) drugs cisplatin and carboplatin are heavily employed in chemotherapy regimens; however, similar to other classes of drugs, a number of intrinsic and acquired resistance mechanisms hamper their effectiveness. The method by which Pt drugs enter cells has traditionally been attributed to simple passive diffusion. However, recent evidence suggests a number of active uptake and efflux mechanisms are at play, and altered regulation of these transporters is responsible for the reduced accumulation of drug in resistant cells. This review suggests a model that helps reconcile the disparate literature by describing multiple pathways for Pt-containing drugs into and out of the cell.
Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells. [Mol Cancer Ther 2008;7(9):3081 -91]
Currently 5-fluorouracil (5-FU) plays a central role in the chemotherapeutic regimens for colorectal cancers and thus it is important to understand the mechanisms that determine 5-FU sensitivity. The expression profiles of human colon cancer cell line DLD-1, its 5-FUresistant subclone DLD-1/FU and a futher 21 types of colon cancer cell lines were compared to identify the novel genes defining the sensitivity to 5-FU and to estimate which population of genes is responsible for 5-FU sensitivity. In the hierarchical clustering, DLD-1 and DLD-1/FU were most closely clustered despite over 100 times difference in their 50% inhibitory concentration of 5-FU. In DLD-1/FU, the population of genes differentially expressed compared to DLD-1 was limited to 3.3%, although it ranged from 4.8% to 24.0% in the other 21 cell lines, thus indicating that the difference of 5-FU sensitivity was defined by a limited number of genes. Next, the role of the cellular inhibitor of apoptosis 2 (cIAP2) gene, which was up-regulated in DLD-1/FU, was investigated for 5-FU resistance using RNA interference. The downregulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after fluorouracilbased chemotherapy. Although the association between drug sensitivity and the IAP family in colorectal cancer has not yet been discussed, cIAP2 may therefore play an important role as a target therapy in colorectal cancer. (Cancer Sci 2009; 100: 903-913) 5-fluorouracil (5-FU) is an anticancer drug that has been mainly used in the treatment of colorectal cancers. Recently, 5-FU has been combined with oxaliplatin or irinotecan as the first-line treatment for advanced colorectal cancers and these have significantly improved the response rates to 40-50% and prolonged overall survival.(1,2) Furthermore, novel biological agents including monoclonal antibodies such as cetuximab, which is an antibody against epidermal growth factor receptor (EGFR), and bevacizumab, which is an antibody against vascular endothelial growth factor, have been shown to provide additional clinical benefit for patients with metastatic colorectal cancers.(3-5) However, there are still a large number of patients who do not benefit from the present treatments because of anticancer drug resistance. Elucidating the mechanisms by which 5-FU resistance arises in colorectal cancer therefore remains an important issue for either overcoming or predicting such resistance.5-FU is an analog of uracil and is rapidly incorporated into the cells using the same transport system as uracil.(6) Subsequently, 5-FU is converted into active metabolites which disrupt the action of thymidylate synthetase (TS) and RNA synthesis. TS and 5-FUmetabolizing enzymes such as dihydropy...
We have recently identified that rat organic anion transporters, polypeptide2 (oatp2) and oatp3, both of which transport thyroid hormones. However, in humans the molecular organization of the organic anion transporters has diverged, and the responsible molecule for thyroid hormone transport has not been clarified, except for human liver-specific transporter (LST-1) identified by us. In this study we isolated and characterized a novel human organic anion transporter, OATP-E from human brain. The isolated complementary DNA encodes a polypeptide of 722 amino acids with 12 transmembrane domains. A rat counterpart, oatp-E, was also identified. Homology analysis and the phylogenetic tree analysis revealed that OATP-E/oatp-E is a subfamily of the organic anion transporter. Human OATP-E transported 3,3',5-triiodo-L-thyronine (K(m), 0.9 microM), thyronine, and rT(3) in a Na(+)-independent manner. Although the clone was isolated from the brain, OATP-E messenger RNA was abundantly expressed in various peripheral tissues. The rat counterpart, oatp-E, also transported 3,3',5-triiodo-L-thyronine. In addition, in this study we revealed that human OATP, which is exclusively expressed in the brain, transported 3,3',5-triiodo-L-thyronine (K(m), 6.5 microM), T(4) (K(m), 8.0 microM), and rT(3). These data suggest that in humans, several different molecules are involved in transporting thyroid hormone: OATP in the brain, LST-1 in the liver, and OATP-E in peripheral tissues.
Development of cisplatin resistance in cancer cells appears to be a consequence of multiple epigenetic alterations in genes involved in DNA damage repair, proto-oncogenes, apoptosis, transporters, transcription factors, etc. In this work, we found that expression of the hypothetical transmembrane protein TMEM205 (previously known as MBC3205) is associated with cisplatin resistance. TMEM205 was first detected by functional cloning from a retroviral cDNA library made from human cisplatin-resistant (CP-r) cells. TMEM205 is predicted to be a transmembrane protein, but its expression, localization, and function have not previously been investigated. A polyclonal antibody directed to the TMEM205 protein was raised in our laboratory. Using this antibody, it was demonstrated that this protein is located at the cell surface. Its expression is increased in our cisplatin-selected CP-r cell lines, as demonstrated by immunoblotting, confocal examination and immuno-electron microscopy. Stable transfection of the TMEM205 gene confers resistance to cisplatin by approximately 2.5-fold. Uptake assays with Alexa Fluor-cisplatin showed reduced accumulation in CP-r KB-CP.3 and KB-CP.5 cells, and in TMEM205-transfected cells. Analysis of TMEM205 expression profiles in normal human tissues indicates a differential expression pattern with higher expression levels in the liver, pancreas, and adrenal glands. These results indicate that a novel mechanism for cisplatin resistance is mediated by TMEM205, and also suggest that overexpression of TMEM205 in CP-r cells may be valuable as a biomarker or target in cancer chemotherapy.
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