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Anticancer agents that counteract tumor glycolysis.

ABSTRACT: Can we consider cancer to be a "metabolic disease"? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have increased needs for both energy and biosynthetic intermediates to support their growth and invasiveness. However, their high proliferation rate often generates regions that are insufficiently oxygenated. Therefore, their carbohydrate metabolism must rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the Warburg effect, constitutes a fundamental adaptation of tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that antiglycolytic agents may cause serious side effects toward normal cells. The key to selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anticancer drugs with minimal toxicity. There is growing evidence to support many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant antiglycolytic agents that have been investigated thus far for the treatment of cancer.

SUBMITTER: Granchi C

PROVIDER: S-EPMC3516916 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Anticancer agents that counteract tumor glycolysis.

Granchi Carlotta C Minutolo Filippo F

ChemMedChem 20120608 8

Can we consider cancer to be a "metabolic disease"? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have increased needs for both energy and biosynthetic intermediates to support their growth and invasiveness. However, their high proliferation rate often generates regions that are insufficiently oxygenated. Therefore, their carbohydrate metabolism must rely m ...[more]

PMID: 22684868

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Project description:Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar Ir(I) complexes, such as Crabtree's hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir(III) complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d(6) Ir(III) centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C^C-chelating ligands can even stabilize Ir(IV) and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar Ir(I) complexes because of their structural and electronic similarity to Pt(II) anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich Ir(III) anticancer complexes. These complexes with the formula [(Cp(x))Ir(L^L')Z](0/n+) (with Cp* or extended Cp* and L^L' = chelated C^N or N^N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form Ir(III)-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert Ir(III) complexes as potent kinase inhibitors. Octahedral cyclometalated Ir(III) complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action.

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Anticancer agents that counteract tumor glycolysis.

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Anticancer agents that counteract tumor glycolysis.

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