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Review
. 2020 Dec;1874(2):188457.
doi: 10.1016/j.bbcan.2020.188457. Epub 2020 Oct 21.

Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer

Kalpana Tilekar  1 , Neha Upadhyay  1 , Cristina V Iancu  2 , Vadim Pokrovsky  3 , Jun-Yong Choe  2 , C S Ramaa  4
Affiliations
Review

Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer

Kalpana Tilekar et al. Biochim Biophys Acta Rev Cancer. 2020 Dec.

Abstract

Cancer research of the Warburg effect, a hallmark metabolic alteration in tumors, focused attention on glucose metabolism whose targeting uncovered several agents with promising anticancer effects at the preclinical level. These agents' monotherapy points to their potential as adjuvant combination therapy to existing standard chemotherapy in human trials. Accordingly, several studies on combining glucose transporter (GLUT) inhibitors with chemotherapeutic agents, such as doxorubicin, paclitaxel, and cytarabine, showed synergistic or additive anticancer effects, reduced chemo-, radio-, and immuno-resistance, and reduced toxicity due to lowering the therapeutic doses required for desired chemotherapeutic effects, as compared with monotherapy. The combinations have been specifically effective in treating cancer glycolytic phenotypes, such as pancreatic and breast cancers. Even combining GLUT inhibitors with other glycolytic inhibitors and energy restriction mimetics seems worthwhile. Though combination clinical trials are in the early phase, initial results are intriguing. The various types of GLUTs, their role in cancer progression, GLUT inhibitors, and their anticancer mechanism of action have been reviewed several times. However, utilizing GLUT inhibitors as combination therapeutics has received little attention. We consider GLUT inhibitors agents that directly affect glucose transporters by binding to them or indirectly alter glucose transport by changing the transporters' expression level. This review mainly focuses on summarizing the effects of various combinations of GLUT inhibitors with other anticancer agents and providing a perspective on the current status.

Keywords: Cancer; Combination strategy; Drug synergy; GLUT inhibitors; Glucose transporters (GLUTs).

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Conflict of interest statement

Conflict of interest: Authors declares no conflict of interest.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Figures

Figure 1.
Figure 1.
Pictorial representation of the preclinical evaluation of the combinations of GLUT inhibitors with other chemotherapeutic agents in various types of cancers.
Figure 2.
Figure 2.
Chemical structures of the natural GLUT inhibitors that have been studied for combination anticancer effects.
Figure 3.
Figure 3.
Chemical structures of the synthetic, small molecule, GLUT inhibitors that have been studied for combination anticancer effects.
Figure 4.
Figure 4.. The schematic representation of glycolytic and mitochondrial pathways and various enzymes that can be targeted.
The combination of GLUT inhibitors with PDH and GLS inhibitors has already been evaluated (marked in yellow) and further combination studies with HK, PFK, enolase, LDH, and IDH inhibitors (marked in green) can be assumed to have synergistic effects and to overcome metabolic plasticity of tumors. The combination studies with enzymes involved in lipid metabolism/lipogenesis (marked in blue dotted square) can also be conducted to determine synergy, FASN-Fatty acid synthase. Dashed arrow indicates there are more than one steps which are not shown in figure.
Figure 5.
Figure 5.. The two-compartment model of cancer cell metabolic reprogramming and energy production.
Under reduced glycolytic activities, cancer cells trigger ROS (Reactive oxygen) generation which signals the neighbouring fibroblast to undergo enhanced glycolysis leading to metabolic coupling between the neighbouring associated fibroblast and cancer cells, supporting the survival and growth of the cancer cells. The associated fibroblast cell serves as catabolic compartment utilizing glycolysis for the production of energy and TCA cycle intermediates which are further transferred to the cancer cells wherein, they will be utilised for anabolic processes such as generation of building blocks and production of energy through oxidative phosphorylation in mitochondria.
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