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Review
. 2022 Nov 1:13:1035510.
doi: 10.3389/fphar.2022.1035510. eCollection 2022.

An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors

Mithlesh Kumar Temre  1 , Ajay Kumar  2 , Sukh Mahendra Singh  1
Affiliations
Review

An appraisal of the current status of inhibition of glucose transporters as an emerging antineoplastic approach: Promising potential of new pan-GLUT inhibitors

Mithlesh Kumar Temre et al. Front Pharmacol. .

Abstract

Neoplastic cells displayed altered metabolism with accelerated glycolysis. Therefore, these cells need a mammoth supply of glucose for which they display an upregulated expression of various glucose transporters (GLUT). Thus, novel antineoplastic strategies focus on inhibiting GLUT to intersect the glycolytic lifeline of cancer cells. This review focuses on the current status of various GLUT inhibition scenarios. The GLUT inhibitors belong to both natural and synthetic small inhibitory molecules category. As neoplastic cells express multiple GLUT isoforms, it is necessary to use pan-GLUT inhibitors. Nevertheless, it is also necessary that such pan-GLUT inhibitors exert their action at a low concentration so that normal healthy cells are left unharmed and minimal injury is caused to the other vital organs and systems of the body. Moreover, approaches are also emerging from combining GLUT inhibitors with other chemotherapeutic agents to potentiate the antineoplastic action. A new pan-GLUT inhibitor named glutor, a piperazine-one derivative, has shown a potent antineoplastic action owing to its inhibitory action exerted at nanomolar concentrations. The review discusses the merits and limitations of the existing GLUT inhibitory approach with possible future outcomes.

Keywords: GLUT; glutor; neoplastic cells; pan-GLUT inhibitors; tumor metabolism.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Role of GLUTs in the accelerated glycolysis of neoplastic cells. Neoplastic cells display an upregulated expression of GLUTs for increased glucose uptake, which is rapidly metabolized to lactate leading to the production of a high amount of ATP and biosynthetic precursors.
FIGURE 2
FIGURE 2
A typical topographical representation of GLUT (GLUT1). The figure shows the organization of the N and C termini, linker regions, and the 12 transmembrane domains of GLUT, which form an aqueous channel for glucose transport across the membrane.
FIGURE 3
FIGURE 3
Conformational changes of GLUT facilitate glucose transport across the cell membrane. The four conformational changes oscillate between 1) Outside open conformation facilitating loading of glucose; 2) outward open conformation with bound glucose (occluded state); 3) inward open state following release of glucose and 4) shifting back to the outward open glucose-free state to capture of glucose. So basically, there are two main conformations the outside open (OOP) and inside open (IOP) states.
FIGURE 4
FIGURE 4
Regulation of GLUT expression in cancer cells. Indicated extrinsic and intrinsic factors can regulate the expression of GLUTs via the mediators of a plethora of signaling messengers, the blend of which could vary in a cancer-specific manner.
FIGURE 5
FIGURE 5
Major small inhibitory molecules of GLUTs. Figures (A-F) show structural details of small GLUT inhibitory molecules. Most of these molecules have overall common structural organization except few alterations in ring structure, constituent elements and their arrangement.
FIGURE 6
FIGURE 6
A collation of the current GLUT inhibitory approaches. The main GLUT inhibitors belong to both natural and small inhibitory molecule categories. In addition, antisense cDNA, anti-GLUT antibodies, miRNAs, shRNA, and siRNAs constitute additional GLUT inhibitory approaches. GLUT inhibition can be further potentiated by combining the GLUT inhibitors of natural origin and small inhibitory molecule categories.
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