title: Isothiocyanate analogs targeting CD44 receptor as an effective strategy against colon cancer.
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.
authors.affiliation: Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Suniti
authors.initials: S
authors.lastname: Misra
authors.affiliation: Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Shibnath
authors.initials: S
authors.lastname: Ghatak
authors.affiliation: ISTRA, Department of Chemistry, Abeda Inamdar College, University of Pune, Pune 411001, India.
authors.forename: Alok
authors.initials: A
authors.lastname: Vyas
authors.affiliation: Hematology/Oncology Division, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.affiliation: Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Markwald
authors.affiliation: Department of Bioinformatics and Computer Science, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India.
authors.forename: Madhukar
authors.initials: M
authors.lastname: Khetmalas
authors.affiliation: Department of Biomedical Engineering/ND20, The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: McCarthy
authors.affiliation: Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Markku I
authors.initials: MI
authors.lastname: Tammi
authors.affiliation: University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors.forename: Raija H
authors.initials: RH
authors.lastname: Tammi
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwitch
authors.affiliation: ISTRA, Department of Chemistry, Abeda Inamdar College, University of Pune, Pune 411001, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
keywords: Anti-cancer; CD44/hyaluronan; COX–LOX dual inhibition; Colon cancer; Isothiocyanate analogs; Molecular modeling