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Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib

Wen-Hsin Chang1, Ta-Chih Liu, Wen-Kuang Yang

  • 1Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Department of Laboratory Medicine, Kaohsiung Medical University Hospital,Center for Excellence in Environmental Medicine, Kaohsiung, Taiwan.

Cancer Research
|January 13, 2011
PubMed

Insights

The drug amiloride alters cancer gene splicing, impacting apoptosis and potentially treating chronic myelogenous leukemia. It enhances imatinib

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Pharmacology

Background:

  • Amiloride, an antihypertensive drug, is explored for cancer therapy, particularly chronic myelogenous leukemia (CML).
  • Previous understanding of amiloride's effects included pH alteration, but its role in cancer gene modulation was less clear.

Purpose of the Study:

  • To investigate amiloride's mechanism in modulating alternative splicing of cancer-related genes.
  • To determine if amiloride's splicing effects are independent of its known pH-altering properties.
  • To assess amiloride's potential as a therapeutic agent for CML, alone or in combination.

Main Methods:

  • Analysis of alternative splicing patterns of genes like Bcl-x, HIPK3, and BCR/ABL upon amiloride treatment.
  • Investigation of splicing factors, including serine-arginine-rich (SR) proteins and their phosphorylation.
  • Genome-wide alternative splicing detection and assessment of amiloride's impact on apoptotic genes.
  • Evaluation of amiloride's effect on protein levels and cell viability in cancer cell lines (K562, BaF3/Bcr-AblT315I).

Main Results:

  • Amiloride modulates alternative splicing of Bcl-x, HIPK3, and BCR/ABL, independent of significant pH changes.
  • Splicing modulation involves SR proteins, with altered phosphorylation states reversed by okadaic acid.
  • Amiloride regulates other apoptotic genes (APAF-1, CRK, SURVIVIN) and involves Bcl-2 family proteins and MAPK kinases.
  • Amiloride treatment leads to increased cell death in CML models, especially when combined with imatinib.

Conclusions:

  • Amiloride influences alternative splicing of key cancer genes and apoptotic pathways.
  • These findings suggest amiloride's potential as a novel therapeutic strategy for CML.
  • Combination therapy with amiloride and imatinib shows enhanced efficacy in preclinical models.

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