Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics

Abstract

Metabolic reprogramming and altered energetics have become an emerging hallmark of cancer and an active area of basic, translational, and clinical cancer research in the recent decade. Development of effective anticancer therapeutics may depend on improved understanding of the altered cancer metabolism compared to that of normal cells. Changes in glucose transport and glycolysis, which are drastically upregulated in most cancers and termed the Warburg effect, are one of major focuses of this new research area. By taking advantage of the new knowledge and understanding of cancer’s mechanisms, numerous therapeutic agents have been developed to target proteins and enzymes involved in glucose transport and metabolism, with promising results in cancer cells, animal tumor models and even clinical trials. It has also been hypothesized that targeting a pathway or a process, such as glucose transport or glucose metabolism, rather than a specific protein or enzyme in a signaling pathway may be more effective. This is based on the observation that cancer somehow can always bypass the inhibition of a target drug by switching to a redundant or compensatory pathway. In addition, cancer cells have higher dependence on glucose. This review will provide background information on glucose transport and metabolism in cancer, and summarize new therapeutic developments in basic and translational research in these areas, with a focus on glucose transporter inhibitors and glycolysis inhibitors. The daunting challenges facing both basic and clinical researchers of the field are also presented and discussed.

Keywords: Cancer metabolism, Warburg effect, Glycolytic enzymes, Glucose transporters, Translational research

Core tip: Reprogramming of metabolism has been recognized at the beginning of 21^st century as an emerging hallmark of cancer. The Warburg effect is one of the major focuses in the reprogramming. We cannot fully understand or more effectively treat cancer without a better understanding of cancer metabolism. Targeting cancer metabolism, particularly glucose transport and glycolysis, has been shown to be effective in inhibiting cancer growth. This review summarizes recent progresses in developments of therapeutics inhibiting glucose transporters and glycolytic enzymes, provides key information associated with each inhibitor, discusses their promises and problems as well as future challenges and directions of the basic and translational research of the field.