[Increasing sensitivity of leukemia cells to imatinib by inhibiting NHE1 and p38MAPK signaling pathway]

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Leukemia cells, particularly in chronic myelocytic leukemia (CML), often develop resistance to imatinib therapy.
• This resistance is frequently associated with the overexpression of drug efflux pumps like P-glycoprotein (Pgp).
• Intracellular pH regulation plays a role in drug resistance mechanisms.

Purpose of the Study:

• To investigate if inhibiting NHE1 and inducing intracellular acidification can overcome imatinib resistance in leukemia cells.
• To explore the downstream signaling pathways, including BCR/ABL, involved in this resistance.
• To analyze the impact on P-glycoprotein expression and drug accumulation.

Main Methods:

• Assessing mRNA and protein expression of P-glycoprotein (Pgp) and drug accumulation in primary leukemia cells and cell lines (K562/DOX, K562/G01).
• Utilizing intracellular acidification and NHE1 inhibitor (cariporide) treatments.
• Analyzing phosphorylation changes of ERK1/2 and p38 MAPK via Western blot.
• Employing p38 MAPK inhibitor (SB203580) to assess synergistic effects.

Main Results:

• Intracellular acidification or cariporide treatment enhanced imatinib sensitivity in K562/DOX and K562/G01 cells.
• Downregulation of intracellular pH decreased p38 MAPK phosphorylation and altered ERK1/2 phosphorylation in advanced CML patients.
• NHE1 inhibition synergized with p38 MAPK inhibition to reduce Pgp expression and increase drug accumulation.

Conclusions:

• NHE1 inhibition significantly decreases Pgp expression and enhances drug accumulation in advanced CML patient cells.
• Intracellular acidification and NHE1 inhibition can reverse imatinib resistance in leukemia cells.
• The p38 MAPK signaling pathway is critically involved in mediating the effects of NHE1 inhibition on drug resistance.