Misra Suniti, Ghatak Shibnath, Vyas Alok, O'Brien Paul, Markwald Roger R, Khetmalas Madhukar, Hascall Vincent C, McCarthy James B, Karamanos Nikos K, Tammi Markku I, Tammi Raija H, Prestwitch Glenn D, Padhye Subhash
Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
ISTRA, Department of Chemistry, Abeda Inamdar College, University of Pune, Pune 411001, India.
Med Chem Res. 2014 Aug 1;23(8):3836-3851. doi: 10.1007/s00044-014-0958-4.
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.
炎症通路在结直肠癌的肿瘤细胞进展中起重要作用。尽管结肠癌被认为是全球主要的死亡原因之一，但用于有效治疗的药物却非常少。许多研究已经考察了特定的COX-2和5-LOX抑制剂对人类结直肠癌的影响，但异硫氰酸酯（ITSCs）作为参与透明质酸-CD44相互作用的COX-LOX双重抑制剂的作用尚未得到研究。在本研究中，我们报道了一系列含有生物电子等排体硫代半卡巴腙部分的ITSC类似物。这些抑制剂对包括COX-2阳性的HCA-7、HT-29细胞系以及透明质酸合酶-2（Has2）酶过表达的转化肠上皮Apc10.1Has2细胞在内的一组人类结肠癌细胞系有效。具体而言，我们的研究结果表明，HA-CD44v6介导的COX-2/5-LOX信号传导介导存活素的产生，这反过来又支持抗凋亡和化疗抗性，导致结肠癌细胞存活。CD44v6shRNA的过表达以及ITSC处理显著降低了结肠癌细胞的存活率。因此，目前的结果为开发有效的HA合成和CD44v6通路抑制剂提供了机会，从而强调了ITSC类似物作为靶向HA/CD44v6通路的化学预防剂的重要性。
