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Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer

P Taverna1, L Liu, H S Hwang

  • 1Division of Hematology-Oncology, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, OH 44106-4937, USA.

Mutation Research
|October 5, 2001
PubMed

Insights

Methoxyamine (MX) enhances temozolomide (TMZ) chemotherapy by increasing DNA damage in cancer cells. This potentiation, particularly in MMR-deficient cells, leads to DNA fragmentation and apoptosis, overcoming resistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • DNA Repair Mechanisms

Background:

  • DNA mismatch repair (MMR) deficient cancer cells exhibit resistance to temozolomide (TMZ).
  • Methoxyamine (MX), a base excision repair (BER) inhibitor, can sensitize these cells to TMZ.
  • Understanding BER's role in response to TMZ-induced DNA damage is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To investigate the effect of MX on TMZ-induced DNA single-strand breaks (SSB) and double-strand breaks (DSB).
  • To characterize the role of MMR status in the formation of TMZ-induced DNA damage in colon cancer cells.
  • To elucidate the mechanism by which MX potentiates TMZ cytotoxicity, especially in MMR-deficient cells.

Main Methods:

  • Evaluation of TMZ-induced SSB using alkaline elution in SW480 (MMR proficient) and HCT116 (MMR deficient) colon cancer cells.
  • Assessment of TMZ-induced DSB using pulsed-field gel electrophoresis in both cell lines.
  • Analysis of DNA repair protein levels and enzymatic activity in response to TMZ and MX treatment.

Main Results:

  • MX significantly increased TMZ-induced SSB in both MMR proficient and deficient cells.
  • TMZ-induced DSB were dependent on MMR status and time; MMR-deficient cells showed significant DSB only with TMZ plus MX.
  • MX and TMZ combination inhibited DNA cleavage activity, suggesting persistence of apurinic/apyrimidinic sites, leading to DS-DNA fragmentation and apoptosis in MMR-deficient cells.

Conclusions:

  • Methoxyamine potentiates temozolomide cytotoxicity by increasing DNA single-strand breaks and promoting double-strand break formation, particularly in MMR-deficient colon cancer cells.
  • The mechanism involves the persistence of unrepaired apurinic/apyrimidinic sites, leading to significant DNA fragmentation and subsequent apoptotic signaling, thereby overcoming TMZ resistance.

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