Abstract
Tumor heterogeneity and drug resistance pose severe limitations to chemotherapy of colorectal cancers (CRCs) necessitating innovative approaches to trigger multiple cytocidal events for increased efficacy. Here, we developed a hybrid drug called KSS19 by combining the COX-2 selective NSAID rofecoxib with the cis-stilbene found in combretastatin A4 (CA4), a problematic, but potent antimicrotubule and anti-angiogenesis agent. The structural design of KSS19 completely prevented the isomerization of CA4 its biologically inactive trans-form. Molecular modeling showed that KSS19 bound avidly to the COX-2 active site and colchicine –binding site of tubulin, with similar docking scores of rofecoxib and CA4 respectively. KSS-19 showed potent anti-proliferative activity against a panel of colon cancer cell lines; HT29 cells, which are resistant to CA4 were 100 times more sensitive to KSS19. The hybrid drug potently inhibited the tubulin polymerization in vitro and in cells inducing a G2/M arrest and aberrant mitotic spindles. Both the basal and LPS-activated levels of COX-2 in colon cancer cells were highly suppressed by the KSS-19. The cancer cell migration/invasion was inhibited and accompanied by increased E-cadherin levels and activated NF-kB/Snail pathways in KSS19-treated cells. The drug also curtailed the formation of endothelial tubes in three-dimensional cultures of the HUVE cells at 250 nM, indicating strong anti-angiogenic properties. In subcutaneous HT29 colon cancer xenografts, KSS19, as a single agent (25 mg/kg/day) significantly inhibited the tumor growth and downregulated the intratumoral COX-2, Ki-67, the angiogenesis marker CD31, however, the cleaved caspase-3 was elevated. Collectively, KSS19 represents a rational hybrid drug with clinical relevance to CRC.
Highlights
Colorectal cancer (CRC) is ranked as the third most common form of cancer worldwide [1] and the third and second most leading cause of cancer-related deaths in women and men respectively in the UnitedStates [2]
A novel class of compound the hybrid dug engineered in this study (KSS19) was synthesized based on the structures of combretastatin A4 (CA4) and known COX-2 inhibitor rofecoxib (Figure 1)
Since KSS19 contains the pharmacophore of CA4, which is well known to be anti-angiogenic [41], we examined the vascular targeting www.oncotarget.com and anti-angiogenic properties of the hybrid drug both at the cell culture and xenograft levels
Summary
Colorectal cancer (CRC) is ranked as the third most common form of cancer worldwide [1] and the third and second most leading cause of cancer-related deaths in women and men respectively in the UnitedStates [2]. Several microtubule-targeting drugs are in clinical use, there remains a need to identify novel agents that can overcome the limitations of current therapies, including acquired and innate drug resistance and undesired adverse effects [12]. Several agents binding to the colchicine site have been identified as potential anticancer agents and their ability to overcome Pgp/β-III tubulin mediated drug resistance along with their antiangiogenic or antivascular actions have attracted much interest. Most of these compounds have small molecular weights with chemically modifiable functional groups; they are amenable to chemical modification and improvement of pharmacokinetic (PK) properties, efficacy, and reduced toxicity
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