One of the effects of exposing in vitro tumour cell lines to chemotherapy drugs is for them to simply pump them out of the cell following signalling from adjacent cells. Is the signalling mechanism related to the chemical structure of the drug or the apoptosis of the signalling cell, or both?
Different transporter proteins (Organic anion Transporters, OAT; Organic Cation Transporter, OCT, Multi Drug Resistance Proteins, MRP; Multi drug and toxin extrusion proteins, MATEs; P-glycoprotein; PgPs commonly known as MDR1 or ATP Binding cassette sub-family B members) are expressed either in the apical or basolateral side of the concerned tumor cells depending upon the efflux direction of the the chemotherapy drugs.
These classes of proteins are mostly involved for efflux transport of chemotherapy drugs by the tumor cells.
Among many possible pathways of efflux transporter activation, BCRP (ABCG2) activation in cancer stem cells (CSC) had been reported to be linked to increased CD133 expression and AKT activation.
Hu C, Li H, Li J, et al. Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling. Carcinogenesis. 2008;29(12):2289–2297.
The cellular developmental and metabolic processes that increases vesicular trafficking of microfilaments causes increased expression of PgP, an MRP family member of ABC transporters in the cell surface with an increased efflux activity.
Hamdoun AM et al, Dev Biol, Volume 276, Issue 2, 15 December 2004, Pages 452–462
Depending on the chemical structure of the drug (cationic/anionic) and the specific substrates for the transporters (though not too much is known regarding selectivity and specificities) the activation happens.
Since increased expression levels of apoptosis protein expressions in efflux transporter's activation had been positively correlated so apoptotic signaling mechanisms seem to be related in efflux transport activation. Could be both the structure of the chemical substrate/drug and the apoptotic signaling work synergistically.
I do agree with Amritlal Mandal is depending on the nature of the drug and i think the mechanism related mainly to the drug and later on to the apoptosis.
Paclitaxel activates MDR1 gene transcription by inducing the expression level of IL6 an IL8 cytokines. Both of these cytokines have binding site on MDR1 gene promoter. I think it is the structure of chemo drug responsible for inducing the expression of MDR1 gene and also signaling pathway activate by chemo drugs.
I remember having read that the phylogenesis of efflux pump is the line of our animal ancestros that feed on plants, some plants producing several chemical products, alkaloids, and so on, having a toxic acitivty on metazoan cells and bodies, in biology you can't speak about teleology, i.e. this organ is intended for, but we must speak about observational facts: this pump acts by expelling this and that out of cell, gut cells may have a higher efflux pump activity, as the evolutionary pressure leading to the efflux pump activity was toxic molecules of a size tending to be not maintained inside the cell membrane and damaging the cell that can't enter the organism but through aliments.
I have no lab experience, so I can't say more than this speculative ideas about the actual, cellular level issues of efflux pumps, besides that many products intended to block its activity were tested or developed, surprisingly, none seems having outperfomed the good old Verapamil, having a narrow therapeutic index because of its potential cardiac toxicity. Salut +
Integrin mediated cell adhesion also promotes drug efflux, that appears coupled to Calcium influx. We generated an integrin mutant that is highly chemoresistant while bypassing adhesion, but have constitutive high Ca influx and as well efflux of doxorubicin
(Mol Cell Biol. 2013 Nov;33(21):4334-45)
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