Anti‐mitotic activity of colchicine and the structural basis for its interaction with tubulin

Abstract

In this review, an attempt has been made to throw light on the mechanism of action of colchicine and its different analogs as anti-cancer agents. Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potent anti-cancer drugs. Colchicine binds to tubulin in a poorly reversible manner with high activation energy. The binding interaction is favored entropically. In contrast, binding of its simple analogs AC or DAAC is enthalpically favored and commences with comparatively low activation energy. Colchicine-tubulin interaction, which is normally pH dependent, has been found to be independent of pH in the presence of microtubule-associated proteins, salts or upon cleavage of carboxy termini of tubulin. Biphasic kinetics of colchicines-tubulin interaction has been explained in light of the variation in the residues around the drug-binding site on beta-tubulin. Using the crystal structure of the tubulin-DAMAcolchicine complex, a detailed discussion on the pharmacophore concept that explains the variation of affinity for different colchicine site inhibitors (CSI) has been discussed.

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…However, colchicine also reduces pulmonary vascular remodeling (Figure 6), likely due to colchicine's antimitotic effects,14, 35 but that does not fully explain the enhanced RV‐PA coupling in MCT‐colchicine rats. The ability of colchicine to dissociate the very strong relationship between RV afterload and RV function demonstrates that colchicine improves RV‐PA coupling (Figure 7).…”

Screening Anti-Cancer Drugs against Tubulin using Catch-and-Release Electrospray Ionization Mass Spectrometry

“…As reported originally by Diaz and co-workers [16,27,28], the association of colchicine to tubulin appears to be a two-step process-a fast, reversible step, followed by a slow, reversible step, Equation (1):…”

“…These MTAs interact with tubulin so as to stabilize or destabilize the polymeric microtubules, in each case leading to cell cycle arrest. In general, drugs that interact with microtubules are divided in two groups: (1) microtubule stabilizers, which include taxanes [12], epothilones [13], discodermolide [14], and peloruside A [15], and (2) microtubules destabilizers, including colchicinoids [16], vinca alkaloids [17], dolastatin [18], and hemiasterlins [19].…”

“…Colchicine has been widely used to treat gout, familial Mediterranean fever, and auto-inflammatory diseases [22,23]. It is an alkaloid found in Colchium autmnale and Gloriosa superba and is composed of three rings, a trimethoxy benzene ring (ring A), a methoxy tropone ring (ring C), and a seven-membered ring (ring B) [16]. The administration of colchicine inhibits the cell division process through two proposed mechanisms.…”

“…In the first mechanism, referred to as the end-poisoning mechanism, polymerization is inhibited through colchicine binding to the ends of the microtubules, thus preventing the growth of microtubules by sterically blocking further addition of the tubulin dimers. The other mechanism focuses on colchicine binding-induced conformational changes in the tubulin dimers, which leads to the inhibition of microtubule assembly or disassembly of the microtubules [9,16,24]. However, the high concentrations of colchicine required to effectively kill cancer cells also adversely affects nontumoral cells, leading to significant dose-limiting side effects.…”