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Epigenetic reversal of acquired resistance to 5-fluorouracil treatment

Rita Humeniuk1, Prasun J Mishra, Joseph R Bertino

  • 1Department of Medicine and Pharmacology, Robert Wood Johnson Medical School, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.

Molecular Cancer Therapeutics
|April 23, 2009
PubMed

Insights

Acquired resistance to 5-fluorouracil (5-FU) in colorectal cancer can be reversed. Low-dose 5-azadeoxycytidine (DAC), a DNA methylation inhibitor, restored 5-FU sensitivity by increasing UMP kinase levels.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacology

Background:

  • Acquired and intrinsic resistance to 5-fluorouracil (5-FU) limits its clinical efficacy in colorectal cancer.
  • The role of epigenetic alterations, such as gene hypermethylation, in mediating 5-FU resistance is not fully understood.
  • Identifying mechanisms to overcome 5-FU resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the potential of epigenetic modulation to reverse acquired resistance to bolus 5-FU in colorectal cancer.
  • To explore the therapeutic efficacy of 5-azadeoxycytidine (DAC) in overcoming 5-FU resistance.
  • To elucidate the molecular mechanisms underlying DAC-mediated reversal of 5-FU resistance.

Main Methods:

  • Treatment of 5-FU-resistant colorectal cancer cells (HCT-8) and tumor-bearing nude mice with low-dose DAC.
  • Assessment of cellular and tumor sensitivity to 5-FU and 5-fluorouridine following DAC treatment.
  • Quantification of UMP kinase (UMPK) protein and mRNA levels in response to DAC.

Main Results:

  • Low-dose DAC treatment restored sensitivity to 5-FU and 5-fluorouridine in 5-FU-resistant colorectal cancer cells.
  • DAC administration overcame bolus 5-FU resistance in a preclinical mouse model of colorectal cancer.
  • DAC treatment led to increased UMPK protein and mRNA levels, correlating with restored 5-FU sensitivity.

Conclusions:

  • Acquired resistance to bolus 5-FU in colorectal cancer may have an epigenetic origin and can be reversed by DAC.
  • DAC-mediated restoration of 5-FU sensitivity is, at least partly, attributed to the upregulation of UMPK.
  • Methylation inhibitors like DAC represent a promising strategy to overcome clinical 5-FU resistance in colorectal cancer.

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