Microtubule-binding agents: a dynamic field of cancer therapeutics

Abstract

Microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. Agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to DNA as a therapeutic target in cancer. The screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties. In the current search for novel microtubule-binding agents, enhanced tumour specificity, reduced neurotoxicity and insensitivity to chemoresistance mechanisms are the three main objectives.

Box 1

A: Time-lapse sequence analysis of microtubules, using fluorescent-labelled tubulin microinjected into human mammamy adenocarcinoma MCF7 cells B: Reduced length changes of individual microtubules in the presence of taxol show suppression of microtubule dynamic instability by taxol

Box 1

A: Time-lapse sequence analysis of microtubules, using fluorescent-labelled tubulin microinjected into human mammamy adenocarcinoma MCF7 cells B: Reduced length changes of individual microtubules in the presence of taxol show suppression of microtubule dynamic instability by taxol

Figure 1. Chemical structures of microtubule binding agents according to binding domains

This figure shows the extreme chemical diversity as well as the complexity of many of these agents. The complex structure of certain natural compounds explains the difficulty encountered by chemists to perform total synthesis of these molecules.

Figure 1. Chemical structures of microtubule binding agents according to binding domains

This figure shows the extreme chemical diversity as well as the complexity of many of these agents. The complex structure of certain natural compounds explains the difficulty encountered by chemists to perform total synthesis of these molecules.

Figure 2. Microtubule formation and binding sites of microtubule inhibitors

Fig 2A. Soluble tubulin dimers containing one alpha tubulin peptide and one beta tubulin peptide polymerize to form a “nucleus”. Additional dimers are added head-to-tail and the resulting microtubules are highly dynamic structures containing a (+) end characterized by an exposed β tubulin peptide and a (−) end characterized by an exposed α tubulin peptide. Fig 2B. Binding sites of microtubule inhibitors. While vinca alkaloids bind to microtubule ends, colchicine binds to soluble dimers which can be incorporated within the microtubules. Taxanes bind along the interior surface of the microtubules.

Figure 2. Microtubule formation and binding sites of microtubule inhibitors

Fig 2A. Soluble tubulin dimers containing one alpha tubulin peptide and one beta tubulin peptide polymerize to form a “nucleus”. Additional dimers are added head-to-tail and the resulting microtubules are highly dynamic structures containing a (+) end characterized by an exposed β tubulin peptide and a (−) end characterized by an exposed α tubulin peptide. Fig 2B. Binding sites of microtubule inhibitors. While vinca alkaloids bind to microtubule ends, colchicine binds to soluble dimers which can be incorporated within the microtubules. Taxanes bind along the interior surface of the microtubules.