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

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Abstract

Inflammatory pathway plays an important role in tumor cell progression of colorectal cancers. Although colon cancer is considered as one of the leading causes of death worldwide, very few drugs are available for its effective treatment. Many studies have examined the effects of specific COX-2 and 5-LOX inhibitors on human colorectal cancer, but the role of isothiocyanates (ITSCs) as COX–LOX dual inhibitors engaged in hyaluronan–CD44 interaction has not been studied. In the present work, we report series of ITSC analogs incorporating bioisosteric thiosemicarbazone moiety. These inhibitors are effective against panel of human colon cancer cell lines including COX-2 positive HCA-7, HT-29 cells lines, and hyaluronan synthase-2 (Has2) enzyme over-expressing transformed intestinal epithelial Apc10.1Has2 cells. Specifically, our findings indicate that HA-CD44v6-mediated COX-2/5-LOX signaling mediate survivin production, which in turn, supports anti-apoptosis and chemo-resistance leading to colon cancer cell survival. The over-expression of CD44v6shRNA as well as ITSC treatment significantly decreases the survival of colon cancer cells. The present results thus offer an opportunity to evolve potent inhibitors of HA synthesis and CD44v6 pathway and thus underscoring the importance of the ITSC analogs as chemopreventive agents for targeting HA/CD44v6 pathway.

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Acknowledgments

This work was supported by 1R03CA167722-01A1 (to S. M. and S. G.), P20RR021949 (to S. G.), P20RR016434 (to S. M., S. G., and R. R. M.), P20RR16461-05 (to S. G., and R. R. M.), HL033756-24, 1 P30AR050953 (to V. C. H.), EPS 0903795 (to S. M.), and MCRC 39919 (to S. G. and S. M.). S. P. acknowledges Mr. P. A. Inamdar and Dr. E. M. Khan for their keen interest and encouragement. We thank Dr. Carla De Giovanni (University of Bologna, Bologna, Italy) for Apc10.1 cells.

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Authors and Affiliations

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

    Suniti Misra, Shibnath Ghatak & Roger R. Markwald

  2. ISTRA, Department of Chemistry, Abeda Inamdar College, University of Pune, Pune, 411001, India

    Alok Vyas & Subhash Padhye

  3. Hematology/Oncology Division, Medical University of South Carolina, Charleston, SC, 29425, USA

    Paul O’Brien

  4. Department of Bioinformatics and Computer Science, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, 411033, India

    Alok Vyas & Madhukar Khetmalas

  5. Department of Biomedical Engineering/ND20, The Cleveland Clinic Foundation, Cleveland, OH, USA

    Vincent C. Hascall

  6. Department of Laboratory Medicine and Pathology, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA

    James B. McCarthy

  7. Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece

    Nikos K. Karamanos

  8. University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Markku I. Tammi & Raija H. Tammi

  9. Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA

    Glenn D. Prestwitch

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  1. Suniti Misra
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Correspondence to Shibnath Ghatak or Subhash Padhye.

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Suniti Misra, Shibnath Ghatak, and Alok Vyas contributed equally to this work.

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Misra, S., Ghatak, S., Vyas, A. et al. Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer. Med Chem Res 23, 3836–3851 (2014). https://doi.org/10.1007/s00044-014-0958-4

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