Among the unfortunately (too) large set of chemoresistance mechanisms in cancer cells is the so "popular" ABC-related pump / MDR phenotype.
While there are hundreds (if not housands) of articles "explaining" how cancer cell poulations are enriched by one or another type of efflux pumps, how efflux pumps "eject" a cytotoxic compound out of the cancer cells, etc..., etc...
...
I request the help of the RG community to provide me with top-ranked articles explaining in a crystal-clear manner the biochemical / molecular pathways that lead cancer cells to activate the ABC system.
Are these molecular / biochemical pathways similar / identical to those leading to the activation of the ABC system in endothelial cells from the BBB, or in the intestinal epithelia of ruminants?
Thank you very much for your attention and your help,
Robert
You should read some of the articles from my boss, Michael Gottesman, here at the NIH/NCI. He and colleagues were the first to discover the role of Pgp in drug resistance.
As a quick answer to your question, I sure nobody truly knows the answer. Activation of the ABC system is probably multifactoral. Perhaps there are genetic and epigenetic mechanisms involved in the upregulation of ABC transporters.
This might give you a head start in your search. -Jim
Thank you very much Jim.
I know the abundant literature by Michael.
I just hoped that someone would be able to provide me with a response, even partial (with articles) explaining how switch on the ABC system once a cancer cell is insulted by a cytotoxic compound.
I fully share your views about the fact that activation of the ABC system must be multifactorial, as well as the "activation" of a cancer.
But after several decades of research, I hope that someone on Earth could bring me one "factor" that activates ABC (with real published proofs about the biochemical / molecular pathways).
Thank you for your time,
Robert
PS: so unfortunately, I have no yet a head start for my search ...
Dear Robert,
i.e. acidosis is one.
Thews, 2006, neoplasia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578510/
Best
Daniel
Thank you so much Daniel!
This is gorgious!!
I can thus make a link with the "old" articles (here attached) about ph and cancer!
Once more, thank you so much.
Robert
While pH is certainly a factor, I also think that the cells are capable of sorting and concentrating drugs and then expel that sorted pack out as vesicles. I have two videos associated with the paper below, one for Hoechst33342 and another for high dose cisplatin. PS: these cells also respond to pH ie. acidic pH increase survival after apoptosis. Please see figure-8b, where blebbishields lose Pgp (activated) and also compare the same panel where the in vivo blebbishield derived tumor (BSE2 tumor tissue) has increased Pgp compared to parental tumor (RT4P tumor tissue).
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: ...
Thank you so much Goodwin.
I am running to boring meetins, and then early afternoon I will read with more than great interest your article!
And certainly back to you soon.
Best regards
Robert
Dear Goodwin,
Your article (the one you attached in your previous response) is actually gorgious!!
I learned a lot and I encounrage RG members interested by "my question" to have an in-depth reading of your article!
Take care!
Robert
More recent article for Goodwin Jinesh G
Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis
http://www.nature.com/articles/cddiscovery20163
Thank you Ahmed, but I do not see in this article the relationship with the activation of the MDR phenotype, or at least with the P-gp.
Best regards
Robert
It seems that tumors exploit acidic microenvironment to induce anaerobic gycolysis pathway as a resource for anabolic blocks of nucleotides, at the expense of normal cells.
While the loss of homeostasis have been occurring, under the effect of cooperating genetic & epigenetic mechanisms, dysregulation of everything will ensue.
I have no specific explanation for activation of MDR phenotype, but it is one of aspects of a generalized loss of cellular homeostasis
Yes Ahmed, I know this topic ...
But we are here very far from my initial question!
Best regards
Robert
Dear Friends,
I have published a paper recently.
it shows the attitude of stem cells researchers.
All the best!
Mahdi.
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