Multidrug Resistance Protein‐4 Influences Aspirin Toxicity in Human Cell Line

Abstract

Overexpression of efflux transporters, in human cells, is a mechanism of resistance to drug and also to chemotherapy. We found that multidrug resistance protein-4 (MRP4) overexpression has a role in reducing aspirin action in patients after bypass surgery and, very recently, we found that aspirin enhances platelet MRP4 levels through peroxisome proliferator activated receptor-α (PPARα). In the present paper, we verified whether exposure of human embryonic kidney-293 cells (Hek-293) to aspirin modifies MRP4 gene expression and its correlation with drug elimination and cell toxicity. We first investigated the effect of high-dose aspirin in Hek-293 and we showed that aspirin is able to increase cell toxicity dose-dependently. Furthermore, aspirin effects, induced at low dose, already enhance MRP4 gene expression. Based on these findings, we compared cell viability in Hek-293, after high-dose aspirin treatment, in MRP4 overexpressing cells, either after aspirin pretreatment or in MRP4 transfected cells; in both cases, a decrease of selective aspirin cell growth inhibition was observed, in comparison with the control cultures. Altogether, these data suggest that exposing cells to low nontoxic aspirin dosages can induce gene expression alterations that may lead to the efflux transporter protein overexpression, thus increasing cellular detoxification of aspirin.

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

“…5 Recently, we demonstrated that aspirin modulates MRP4 expression through a PPARα-dependent mechanism 6 and that its upregulation is an adaptive response to limit intracellular toxicity. 7 Aspirin MRP4-induced over-expression correlates with high onaspirin treatment residual platelet reactivity, that is due in part to incomplete COX-1 inhibition, and in part to COX-1-independent mechanisms. 8 The PLATO trial group recently suggested a phenomenon called platelet adaptome, that originating in megakaryocytes given their diversity and ability to respond at the molecular level to pharmacological inhibition.…”

“…Recently, we demonstrated that aspirin modulates MRP4 expression through a PPARα‐dependent mechanism6 and that its upregulation is an adaptive response to limit intracellular toxicity 7. Aspirin MRP4‐induced over‐expression correlates with high on‐aspirin treatment residual platelet reactivity, that is due in part to incomplete COX‐1 inhibition, and in part to COX‐1–independent mechanisms 8…”

Are Normal Kidney Cells Influenced by Aspirin in Cell Culture?

“…Studies show that aspirin may influence proliferation of cells including cancer cells. [8], [9] Studies also suggest that exposing cells to low nontoxic aspirin dosages could induce gene expression alterations that may lead to the efflux transporter protein over-expression, thus increasing cellular detoxification of aspirin [10] ; according to which it is expected that low doses of aspirin not to impair normal cells growth and functions. It has also been shown that aspirin is more effective than diclofenac against the growth of rhabdomyosarcoma cell line.…”

Synthesis and Antiplatelet Activites of Some Derivatives of p-Coumaric Acid

“…Meanwhile, the RS of 4 show similarly low interactions with COX-1 and thromboxane. The best docking poses of ASP and p-coumaric acid derivatives (2)(3)(4)(5) are shown in Fig. 3.…”

“…However, about 15-25 % of patients are known to be resistant to aspirin. In addition, there are side effects in the form of bleeding and neutropenia [4,5].…”