ABSTRACT
Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-ß estradiol analogs as cancer treatment.
Subject(s)
Antimitotic Agents/therapeutic use , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Proliferation/drug effects , Neoplasms/drug therapy , Antimitotic Agents/classification , Biomarkers, Tumor/metabolism , Drug Resistance, Neoplasm , Humans , Neoplasms/metabolism , Taxoids/therapeutic use , Vinca Alkaloids/therapeutic useABSTRACT
Antimitotic agents have been the most successful pharmacological agents for the treatment of cancer. The term "antimitotic agent" has traditionally been synonymous with tubulin-targeting compounds, but as a consequence of the large number of new compounds and mechanisms that have been identified recently, a much broader definition is currently needed. This review attempts to provide a broad overview of compounds and their cognate protein targets which result in a block in mitosis. Focus has been placed on agents that act directly on the mitotic machinery rather than on targets further upstream such as growth factor receptors.
Subject(s)
Antimitotic Agents/pharmacology , Biological Products/pharmacology , Actins/metabolism , Animals , Antimitotic Agents/classification , Binding Sites/drug effects , Biological Products/classification , Colchicine/pharmacology , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Humans , Kinesins/antagonists & inhibitors , Microtubule Proteins/antagonists & inhibitors , Phosphoric Monoester Hydrolases/antagonists & inhibitors , Phosphoric Monoester Hydrolases/genetics , Proteasome Inhibitors , Sulfhydryl Compounds/pharmacology , Topoisomerase Inhibitors , Tubulin/drug effects , Vinca Alkaloids/pharmacologyABSTRACT
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.
