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Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer

Suniti Misra1, Shibnath Ghatak1, Alok Vyas2

  • 1Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.

Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents
|July 12, 2014
PubMed

Insights

Isothiocyanates (ITSCs) show promise as dual COX-LOX inhibitors for colorectal cancer. These compounds target the hyaluronan-CD44v6 pathway, reducing cancer cell survival and offering chemopreventive potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Colorectal cancer (CRC) is a leading cause of cancer death with limited treatment options.
  • Inflammation significantly contributes to CRC progression.
  • The hyaluronan-CD44 pathway's role in CRC survival and chemoresistance is increasingly recognized.

Purpose of the Study:

  • To investigate isothiocyanates (ITSCs) as dual cyclooxygenase (COX)-lipoxygenase (LOX) inhibitors.
  • To explore the role of ITSCs in targeting the hyaluronan (HA)-CD44 interaction in colon cancer.
  • To evaluate novel ITSC analogs incorporating a thiosemicarbazone moiety for anticancer activity.

Main Methods:

  • Synthesis and evaluation of novel isothiocyanate (ITSC) analogs.
  • Testing inhibitor efficacy against a panel of human colon cancer cell lines.
  • Assessing the impact on hyaluronan synthase-2 (Has2) enzyme activity.
  • Investigating the role of CD44v6 and downstream signaling pathways.

Main Results:

  • ITSC analogs demonstrated effectiveness against COX-2 positive and Has2 over-expressing colon cancer cells.
  • Findings revealed HA-CD44v6-mediated COX-2/5-LOX signaling drives survivin production, promoting anti-apoptosis and chemoresistance.
  • Over-expression of CD44v6shRNA and ITSC treatment significantly reduced colon cancer cell survival.

Conclusions:

  • ITSC analogs act as potent dual COX-LOX inhibitors targeting the HA-CD44v6 pathway.
  • These compounds effectively inhibit colon cancer cell survival by modulating survivin production.
  • ITSC analogs represent promising chemopreventive agents for targeting the HA/CD44v6 pathway in colorectal cancer.
Keywords:
Anti-cancerCD44/hyaluronanCOX–LOX dual inhibitionColon cancerIsothiocyanate analogsMolecular modeling

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