Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors

Olszewski, Kellen L.; Barsotti, Anthony M.; Xiao, Feng; Momcilovic, Milica; Liu, Kevin G.; Kim, Ji‐In; Morris, Koi; Lamarque, Christophe; Gaffney, Jack; Yu, Xiaobing; Patel, Jeegar; Rabinowitz, Joshua D.; Shackelford, David B.; Poyurovsky, Masha V.

doi:10.1016/j.chembiol.2021.10.007

Cited by 25 publications

(14 citation statements)

References 63 publications

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“…The levels of glycolysis intermediates were clearly reduced by vitamin C treatment ( Figure 3 C and Figure S2C ), further confirming that vitamin C inhibits glucose metabolism. Previous studies have reported that cancer cells undergo metabolic reprogramming to replenish their survival needs when glycolysis is suppressed, including toward mitochondrial OXPHOS [ 22 , 23 ]. Based on these studies, we attempted to rescue glucose metabolism inhibition-induced cell death by supplementing the cells with pyruvate, which provides substrates for the TCA cycle.…”

Section: Resultsmentioning

confidence: 99%

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Kim

Hwang

Lee

et al. 2022

IJMS

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Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/β-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Kim

Hwang

Lee

et al. 2022

IJMS

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“…The head and neck tumor HN0586 was about 22% smaller than the control after 42 days, the melanoma tumor ME12217 was 57% smaller after 20 days, and the lung tumor LU6415 was 48% smaller after 15 days. The authors concluded that GLUT inhibitors for cancer treatments would exhibit the best outcomes in TCA cycle deficient tumors [ 90 ].…”

Section: Recent Examples Of Glut Associated Diseasesmentioning

confidence: 99%

Importance of GLUT Transporters in Disease Diagnosis and Treatment

Ismail

Tanasova

2022

IJMS

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Facilitative sugar transporters (GLUTs) are the primary method of sugar uptake in all mammalian cells. There are 14 different types of those transmembrane proteins, but they transport only a handful of substrates, mainly glucose and fructose. This overlap and redundancy contradict the natural tendency of cells to conserve energy and resources, and has led researchers to hypothesize that different GLUTs partake in more metabolic roles than just sugar transport into cells. Understanding those roles will lead to better therapeutics for a wide variety of diseases and disorders. In this review we highlight recent discoveries of the role GLUTs play in different diseases and disease treatments.

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“…Other crucial small molecule inhibitors of GLUT include GLUTi1 and GLUTi2 ( Kapoor et al, 2016 ), compound 3 ( Siebeneicher et al, 2016a ), compound 15b ( Liu et al, 2020 ), PUG1 ( Ung et al, 2016 ), KL-11743 ( Olszewski et al, 2022 ), and NV5440 (S. A. Kang et al, 2019 ) which belong to diverse families of chemicals and exert limited GLUT isoform inhibitory potential and have high IC50 values, so the possibilities of in vivo toxicity remains a concerning issue.…”

Section: Inhibition Of Glut As a Promising Anti-cancer Approachmentioning

confidence: 99%

“…Moreover, several studies have been conducted to evaluate the outcome of combining various GLUT inhibitors for achieving optimum inhibition of glucose uptake ( Tilekar et al, 2020 ). The most promising of such combinations with successful antineoplastic outcomes include combination of GLUT inhibitors like cytochalasin B, WZB117 and its derivatives, BAY-876, silibinin, glutor, STF-31 and phloretin with other conventional anticancer drugs like doxorubicin, curcumin, etoposide, cisplatin, 5-fluorouracil, vincristine, cytarabine, oxaliplatin, paclitaxel and antimycin A ( Liu et al, 2012 ; Tsakalozou et al, 2012 ; Li et al, 2019 ; Trendowski, 2015 ; Trendowski, 2015 ; Kapoor et al, 2016 ; Chen et al, 2017 ; Reckzeh et al, 2019 ; Zambrano et al, 2019 ; Barbosa and Martel, 2020 ; Joly et al, 2020 ; Tilekar et al, 2020 ; Wu et al, 2020 ; Shriwas et al, 2021 ; Olszewski et al, 2022 ; Temre et al, 2022 ; Weng et al, 2022 ) to name a few such representative anticancer drugs in cancers of diverse origins. Nevertheless, inhibitors of other molecules and/or pathways have also been combined with GLUT inhibitors to achieve fruitful antineoplastic effects ( Tsakalozou et al, 2012 ; Tilekar et al, 2020 ; Weng et al, 2022 ).…”

Section: Inhibition Of Glut As a Promising Anti-cancer Approachmentioning

confidence: 99%

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

2022

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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.

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Inhibition of glucose transport synergizes with chemical or genetic disruption of mitochondrial metabolism and suppresses TCA cycle-deficient tumors

Cited by 25 publications

References 63 publications

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Vitamin C Suppresses Pancreatic Carcinogenesis through the Inhibition of Both Glucose Metabolism and Wnt Signaling

Importance of GLUT Transporters in Disease Diagnosis and Treatment

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

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