A transition state analogue of 5'-methylthioadenosine phosphorylase induces apoptosis in head and neck cancers

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Indranil Basu1, Grace Cordovano, Ishita Das

  • 1Biochemistry, Pathology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.

The Journal of Biological Chemistry
|June 6, 2007
PubMed

Insights

Methylthio-DADMe-immucillin-A targets 5'-methylthioadenosine phosphorylase (MTAP) to induce apoptosis in head and neck cancer cells. This selective inhibition offers potential for treating cancers sensitive to reduced CpG island methylation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • 5'-methylthioadenosine phosphorylase (MTAP) recycles 5'-methylthioadenosine (MTA).
  • MTAP inhibition disrupts cellular metabolism and can impact cancer cell survival.
  • Aberrant DNA methylation is a hallmark of various cancers, including head and neck squamous cell carcinoma.

Purpose of the Study:

  • To investigate the efficacy of Methylthio-DADMe-immucillin-A (MT-DADMe-ImmA) as an MTAP inhibitor.
  • To determine the mechanism of MT-DADMe-ImmA-induced apoptosis in cancer cells.
  • To evaluate the therapeutic potential of MT-DADMe-ImmA in head and neck squamous cell carcinoma.

Main Methods:

  • In vitro cell culture experiments using head and neck squamous cell carcinoma lines (FaDu, Cal27), normal fibroblasts, and a breast cancer line (MCF7).
  • Treatment with MT-DADMe-ImmA and MTA, followed by assessment of apoptosis, polyamine levels, and mitochondrial membrane potential.
  • Analysis of DNA methylation using CpG island microarrays and in vivo studies using a mouse xenograft model.

Main Results:

  • MT-DADMe-ImmA in combination with MTA selectively induced apoptosis in FaDu and Cal27 cells, but not in normal fibroblasts or MCF7 cells lacking MTAP.
  • Apoptosis was mediated by loss of mitochondrial inner membrane potential, G(2)/M arrest, and caspase activation.
  • Treatment led to decreased CpG island methylation in FaDu cells, and MT-DADMe-ImmA treatment resulted in tumor remission in a mouse xenograft model.

Conclusions:

  • MT-DADMe-ImmA, in conjunction with MTA, demonstrates selective anti-cancer activity against head and neck squamous cell carcinoma.
  • The drug's mechanism involves MTAP inhibition, subsequent MTA accumulation, and induction of apoptosis.
  • Reduced CpG island methylation is associated with MT-DADMe-ImmA's efficacy, suggesting its potential as a targeted cancer therapy.

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