Abstract
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.
Highlights
In Canada, it is estimated that 187, 600 people will be diagnosed with cancer and 75, 500 people will die from cancer in 2013 [1]
Non-cancerous normal human fibroblasts (NHFs) were used as the normal cell counterpart in this study to ascertain the selectivity of the compounds to cancer cells
It was observed that Green 1 was selective to cancer cells, as the viability of PANC1 cells was modestly reduced while the viability of NHFs remained unaffected
Summary
In Canada, it is estimated that 187, 600 people will be diagnosed with cancer and 75, 500 people will die from cancer in 2013 [1]. Of the vast number of different types of cancer, pancreatic cancer is one of the most deadly, as it is very aggressive, resistant to treatment, progresses rapidly and has a lack of clear symptoms; it is associated with poor prognosis and late stage diagnosis [2,3]. It is of great importance that a selective, safer and non-toxic alternative to current treatment options is developed for those who suffer with pancreatic cancer. Leukemia is another deadly type of cancer that occurs when blood stem cells in the bone marrow develop into abnormal cells. Treatment options are available, there is still a need to develop a more effective and safer alternative
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