Effects of the multidrug resistance-1 gene on drug resistance in primary immune thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune disorder that is characterized by low platelet count. Glucocorticoids (GCs) resistance is a great challenge in the treatment of ITP. P-glycoprotein (P-gp) is a widely studied protein, which is associated with drug resistance. However, in ITP, the functional activity and immune regulation mechanism of P-gp remain uncertain. In this study, we evaluated the expression and functional activity of P-gp in different lymphocyte subsets, explored the correlation between P-gp function and GCs resistance and investigated the role of P-gp in ITP pathogenesis. Results indicated that the functional activity and mRNA level of P-gp were significantly higher in GCs-nonresponsive patients than in GCs-responsive patients with ITP. However, these differences in P-gp were only significant in CD8 T cells. P-gp function was related to disease activity rather than GCs therapy. P-gp was involved in secreting granzyme B and perforin, maintaining autoreactive lymphocytes survival and enhancing autologous platelets lysis in ITP. In conclusion, over-functional P-gp might play an important role in the pathogenesis of ITP and induce GCs resistance in nonresponsive ITP patients. The blockage of P-gp could be a promising therapeutic approach for GCs-resistant patients with ITP.

Cepharanthine synergistically promotes methylprednisolone pharmacodynamics against human peripheral blood mononuclear cells possibly via regulation of P-glycoprotein/glucocorticoid receptor translocation

“…A limitation of our study is the lack of PBMCs to confirm the synergistical effect of CEP and MP and their action mechanism. It is possible to further investigate the role of CEP on MP pharmacodynamics and their action mechanism by using PBMCs with over-functional P-glycoprotein isolated from non-responsive ITP patients [ 12 ]. Although, Cepharanthin ® combined with GC were confirmed to be useful in the management of chronic ITP [ 1 , 8 ], we look forward to new clinical reports which compare the effects of CEP and Cepharanthin ® combined with GC for non-responsive ITP patients.…”

“…It transports a variety of substrates, including GC, out of the immune cells [ 11 ]. Over-functional P-glycoprotein has been reported to play an important role in the pathogenesis of ITP and to reduce the immunosuppressive efficacy of GCs in non-responsive ITP patients [ 12 ]. Our previous study suggested that CEP strongly inhibited P-glycoprotein function in T lymphocytic leukemia daunorubicin resistant MOLT-4 cells (MOLT-4/DNR), whereas isotetrandrine and berbamine, the other two components of Cepharanthin ® , showed extremely weak inhibitory effects on P-glycoprotein function [ 13 ].…”

Methotrexate Combined with 4-Hydroperoxycyclophosphamide Downregulates Multidrug-Resistance P-Glycoprotein Expression Induced by Methotrexate in Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the JAK2/STAT3 Pathway

“…Moreover, P-gp regulation is complex. Factors, such as drugs, cytokines, gene polymorphisms, and oncogenes, can affect the expression of P-gp [ 6 ]. In addition to serving as the primary treatment for RA, MTX is a specific substrate of P-gp [ 7 ].…”