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.