Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux
Saroj P. Mathupala
Affiliation: Department of Neurological Surgery and Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R. Road, 607 HWCRC, Detroit, MI 48035, USA.
Metabolism in tumors deviates significantly from that of normal tissues. Increasingly, the underlying aberrant metabolic pathways are being considered as novel targets for cancer therapy. Denoted “metabolic targeting”, small molecule drugs are under investigation for focused inhibition of key metabolic steps that are utilized by tumors, since such inhibitors should harbor minimal toxicity towards surrounding normal tissues. This review will examine the primary biochemical pathways that tumors harness to enhance their bioenergetic capacity, which in turn, help their rapid proliferation and metastasis within the host. It is hoped that “metabolite-mimetic” drugs can be utilized to interfere with metabolic flux pathways active within the tumor, and across tumor-microenvironment boundary. In fact, the major pathways of mammalian metabolism, i.e., the carbohydrate, amino-acid, and fatty-acid metabolic pathways have been examined as putative targets for drug development, with some drug candidates advancing to phase II/III stages. In this regard, glucose metabolism, i.e., the glycolytic pathway - that predominates the bio-energetic flux in tumors, and the associated mitochondrial metabolism have received the most attention as suitable “druggable” targets, focused either at the pathway enzymes or at the plasma-membrane-bound metabolite transporters. Outlined in this review are pre-clinical studies that have led to the discovery of promising drug candidates to target tumor-metabolic flux, and ensuing patents, with descriptions of the biochemical rationale for the combinatorial strategy of a particular metabolic pathway-drug candidate pair.
Keywords: Metabolism, glycolysis, tumor, mitochondria, metabolic targeting, metabolite-mimetics, oxidative phosphorylation, glucose transporters, positron emission tomography, tumori-genesis, UDP-Gal, phospho-fructokinase, aldolase, nitrosoureas, cisplatins, taxanes, IGFR, GAPDH, PDK, pyruvate dehydrogenase complex, PDH, dichloroacetate, diRuthenium, HIF-1, Drosophila ultrabithorax gene, ARNT, technetium, SMMRs, malonyl-CoA decarboxylase, fatty acid synthase, UCP, glyco-randomization, thioredoxin, Tavocept, dimesna, BNP7787
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