Normal cells human cell types express different ABC transporters that when over expressed in the cancer cell render the cancer cell with an MDR phenotype. However, the genome of the normal cell contains genes that express different efflux pumps that are selectively over-expressed in different cancer cell lines. One would expect that in a cancer cell where unexpressed genes of the normal cell are expressed, the cancer cell, would express more than one efflux pump responsible for the MDR phenotype of the cancer cell. Yet, with the possible exception of CACO cells that have been claimed to express at least two distinct ABC transporters that extrude cytotoxic drugs (Guo A, Marinaro W, Hu P, Sinko PJ. Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT).
Drug Metab Dispos. 2002 Apr;30(4):457-63. PubMed PMID: 11901101.), the literature suggests that only one specific ABC efflux pump is expressed in the cancer cell line. Does anyone know otherwise. And if yes, any evidence for selective suppression of genomes that code for more other efflux pumps within the same cell line?
In the publication "Predicting drug sensitivity and resistance: Profiling ABC
transporter genes in cancer cells", CANCER CELL, 6, 129, 2004 Szakács et al. present the mRNA levels of the 48 known ABC transporters in the NCI 60 cell line panel. In supp info 3 the z-score data can be found.
I am aware of the studies by Szakacs which studied the expression of MRNA in the NCI cell line panel consisting of 60 cell lines. However, the question I asked is for the identify of a cell line other than the CACO line, that expresses more than one efflux pump.
We have profiled (mRNA) ABCB1, ABCC1, ABCG2 and hOCT1 (SLC22A1) in leukemic K562 cells over time, as they gained resistance to the TKI Imatinib, which took a few months. What we observed was a progressive increase of ABCB1 and ABCG2 transporters as cells gained resistance, but then there a progressive reduction of their expression, presumably as other resistance mechanisms kicked in. Our results suggest that induction mechanisms are still present and cells can in fact express more than one ABC transporter. However they also suggest that this expression could be transient, leading once again to the idea that multiple resistance mechanisms occur concomitantly. I think it highly likely that cancer cells express more than one efflux pump at once, but expression could vary according to cellular requirements.
Dear Antonio, I agree with your premise. Indeed the genome for multiple efflux pumps is present in all diploid human cells. However, their expression, unlike the efflux pumps of a bacterium such as E coli which expresses as many as 9 pumps, and as the major AcrAB-tolC is deleted, the remainder are expressed to a much higher level. You are also correct that depending upon where in the spectrum the cancer cell happens to be relevant to the stress created with exposure to a cytotoxic agent (anti-cancer drug), the specific efflux pump or pumps may differ with respect to their level of expression, Of course, this has great significance for adjuvant therapy with cytotoxic drugs since the degree of an effect by an efflux pump inhibitor may differ from efflux pump to efflux pump. What are your thoughts on this?
Dear Antonio, Has the work you described been published and if yes, please send me the reference. Thanks.
Best wishes,
Len
Dear Leonard
We published the work in Leuk Lymphoma. 2011 Oct;52(10):1980-90. doi: 10.3109/10428194.2011.584005. I'me sending you the pdf.
Best regards,
Antonio
Dear Antonio,i would love to add your article for my reference as am a drug designer for multiple drug resistant cells and am stuck.. hope your article could help me out with this , Kindly spare me a copy of the same file...
Truly
Shiva
We had detected P-Glycoprotein and ABCG2 in same cancer cell line.
"Blebbishields, the Emergency Program for Cancer Stem Cells: Sphere Formation and Tumorigenesis after Apoptosis"
Goodwin Jinesh G, Woonyoung Choi, Jay B. Shah, Eugene K. Lee, Daniel Levi Willis, Ashish M. Kamat
https://www.researchgate.net/publication/233742776_Blebbishields_the_Emergency_Program_for_Cancer_Stem_Cells_Sphere_Formation_and_Tumorigenesis_after_Apoptosis
Article Blebbishields, the Emergency Program for Cancer Stem Cells: ...
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