Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer

Synthesis, deposition, and interactions of hyaluronan (HA) with its cellular receptor CD44 are crucial events that regulate the onset and progression of tumors. The intracellular signaling pathways initiated by HA interactions with CD44 leading to tumorigenic responses are complex. Moreover, HA molecules may perform dual functions depending on their concentration and size. Overexpression of variant isoforms of CD44 (CD44v) is most commonly linked to cancer progression, whereas their loss is associated with inhibition of tumor growth. In this review, we highlight that the regulation of HA synthases (HASes) by post-translational modifications, such as O-GlcNAcylation and ubiquitination, environmental factors and the action of microRNAs is important for HA synthesis and secretion in the tumor microenvironment. Moreover, we focus on the roles and interactions of CD44 with various proteins that reside extra- and intracellularly, as well as on cellular membranes with particular reference to the CD44-HA axis in cancer stem cell functions, and the importance of CD44/CD44v6 targeting to inhibit tumorigenesis

Novel Di-Tertiary-Butyl Phenylhydrazones as Dual Cyclooxygenase-2/5- Lipoxygenase Inhibitors: Synthesis, COX/LOX Inhibition, Molecular Modeling, and Insights into Their Cytotoxicities

Although dual inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) enzymes is highly effective than targeting COX or LOX alone, there are only a few reports of examining such compounds in case of colorectal cancers (CRC). In the present work we report that the novel di-tert-butyl phenol-based dual inhibitors DTPSAL, DTPBHZ, DTPINH, and DTPNHZ exhibit significant cytotoxicity against human CRC cell lines. Molecular docking studies revealed a good fit of these compounds in the COX-2 and 5-LOX protein cavities. The inhibitors show significant inhibition of COX-2 and 5-LOX activities and are effective against a panel of human colon cancer cell lines including HCA-7, HT-29, SW480 and intestinal Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressing colon cancer cells, through inhibition of the Hyaluronan/CD44v6 cell survival pathway. Western blot analysis and qRT-PCR analyses indicated that the di-tert-butyl phenol-based dual inhibitors reduce the expression of COX-2, 5-LOX, and CD44v6 in human colon cancer HCA-7 cells, while the combination of CD44v6shRNA and DTPSAL has an additional inhibitory effect on CD44v6 mRNA expression. The synergistic inhibitory effect of Celecoxib and Licofelone on CD44v6 mRNA expression suggests that the present dual inhibitors down-regulate cyclooxygenase and lipoxygenase enzymes through CD44v6. The compounds also exhibited enhanced antiproliferative potency compared to standard dual COX/LOX inhibitor, viz. Licofelone. Importantly, the HA/CD44v6 antagonist CD44v6shRNA in combination with synthetic compounds had a sensitizing effect on the cancer cells which enhanced their antiproliferative potency, a finding which is crucial for the anti-proliferative potency of the novel synthetic di-tert-butyl phenol based dual COX-LOX inhibitors in colon cancer cells