Colchicine is one of the natural compounds with greater capacity to stop the reproduction of cancer cells, but its high toxicity prevents it from being used in extensive treatments such as those required by cancer patients. The chemical modification of colchicine, developed by the Organic Synthesis Group of the Universitat Jaume I, allows reducing toxicity and turning it into a potential anticancer therapeutic agent. The results achieved in the laboratory when applying the compound developed in tumour and non-tumour cell lines have been published in the European Journal of Medicinal Chemistry, and open the door to a next phase for its clinical study.
The coordinator of the Organic Synthesis Group of the UJI, Miguel Carda, explains that some of the compounds synthesized from colchicine have shown less toxicity in non-tumour cell lines, but maintain the antimitotic effectiveness in the case of tumour cells, thus halting the division of the affected cells. In this sense, the researcher Eva Falomir emphasizes that, in addition to this selective ability to act on cancer cells, the new compounds have also been shown to be effective in inhibiting the expression of oncogenes (genes that predispose to cancer), which could expand the therapeutic window of these colchicine derivatives.
“Tubulin is a key protein in the process of mitosis, in which cell division occurs. Many natural products, such as colchicine, and others used in chemotherapy, target tubulin or microtubules (biopolymers formed by tubulin aggregation). The main problem with antimitotic drugs is their lack of selectivity towards non-cancerous cells, which explains their unwanted side effects”, explains Falomir.
Colchicine is a substance found in plants of the genus Colchicum and was the first agent to inhibit the polymerization of tubulin to be discovered. “Although colchicine is one of the most potent antimitotic drugs, it is not used in chemotherapy because of its high toxicity, which explains the efforts to obtain similar compounds for the treatment of cancer”, explains Carda. The researcher remarks that colchicine is used, indeed, in very small doses in very specific treatments, for example, of acute eruptions of gout, but it is not suitable in diseases that require a longer treatment such as cancer.
The research developed has shown how some of the colchicine derivatives, particularly the haloacetyl ones, show complete inhibition of tubulin polymerization in a manner similar to colchicine. In addition, these colchicine derivatives have been shown to be quite active in regulating negatively oncogenes. These derivatives of colchicine are part of the new therapeutic strategies in oncology aimed at boycotting the mechanisms that tumour cells use for their uncontrolled proliferation. As Carda says: “Before, anti-tumour treatments were very unspecific and caused side effects in other parts of the body not affected by the tumour. Currently, more specific treatments are being sought for each type of cancer, and these new compounds could be applied to personalized therapies that reduce the side effects of oncological treatments”.
The results of the study are collected more informatively in an article published in the journal Scientific Trends, in which Eva Falomir explains, together with the researcher Juan Murga, how “in the same way that the glass shoe transformed the ragged Cinderella into a princess, the haloaroyl unit could transform toxic colchicine into a potential anti-cancer therapeutic agent”. Thus, the compounds designed by the research team of the UJI can be the basis for the development of oncological drugs of high selectivity and low toxicity, by demonstrating a high efficiency to kill cancer cells, and a low toxicity in non-tumour cells.
Bibliographic references:
Marzo-Masa, Ana, Eva Falomir, Juan Murga, Miguel Carda y J. Alberto Marcob (2018). «Effects on tubulin polymerization and down-regulation of c-Myc, hTERT and VEGF genes by colchicine haloacetyl and haloaroyl derivatives», European Journal of Medicinal Chemistry, Volume 150, 25 April 2018, Pages 591-600: https://www.sciencedirect.com/science/article/pii/S022352341830254X?via%3Dihub
Falomir, Eva y Juan Murga. «Colchicine: The Cinderella of Anticancer Drugs», Science Trend: https://sciencetrends.com/colchicine-the-cinderella-of-anticancer-drugs/
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