Colchicine, a
natural product of Colchicum autumnae currently used for
gout treatment, is a
tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This
tubulin-targeting property has lead researchers to investigate the potential of
colchicine and analogs as possible
cancer therapies. One major study conducted on an analogue of
allocolchicine,
ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel
allocolchicine analogues that hold non-toxic anti-
cancer properties. Currently we have synthesized and evaluated the anti-
cancer activities of two analogues; N-acetyl-O-methylcolchinol (
NSC 51046 or
NCME), which is structurally similar to
ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of
allocolchicine that is isomeric in the A ring.
NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1
pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these
pancreatic cancer cells and E6-1
leukemia cells but not in normal human fibroblasts. Unlike
colchicine and
NSC 51046, Green 1 does not appear to affect
tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased
reactive oxygen species (ROS) production in mitochondria isolated from
pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of
colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in
cancer therapy.