Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil

Chang, Chun-Kai; Chiu, Pei-Fang; Yang, Huiyi; Juang, Yu-Pu; Lai, Yen-Hsun; Lin, Tzung-Sheng; Hsu, Lih‐Ching; Yu, Linda Chia‐Hui; Liang, Pi‐Hui

doi:10.1021/acs.jmedchem.0c00897

Cited by 20 publications

(16 citation statements)

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“…Another strategy would be targeting GLUT transporters to facilitate drug delivery since these transporters were upregulated on the cell surface of various types of cancer. A recent study revealed that a novel drug conjugate of 5-FU and phloretin (a GLUT inhibitor) exhibited better antitumor e cacy than 5-FU alone, with fewer side effects in animal models [10]. Our data illustrated a proof-of-concept for the synergistic effects of targeting glucose pathways with chemotherapy.…”

Section: Discussionmentioning

confidence: 54%

“…The human colorectal adenocarcinoma cell line HT29 (ATCC#HTB-38) was injected into immunode cient mice to establish a xenograft tumor model as previously described [10,15]. Animal protocols were approved by the Institutional Animal Care and Use Committee of NTUCM.…”

Section: Xenograft Mouse Modelsmentioning

confidence: 99%

“…Early work has focused on genetic changes in association with drug metabolism and e ux pathways for chemoresistance [7,8]. Accumulating evidence indicates that an altered cellular bioenergetic status also causes tumor hyperproliferation and resistance to cell death [9,10]. Normal cells rely on oxidative phosphorylation (OXPHOS) to produce energy for fundamental cellular functions, while cancer cells depend on glycolysis as their primary energy source for rapid tumor growth in hypoxic microenvironments or even aerobic conditions, a phenomenon known as the Warburg effect [11,12] .…”

Section: Introductionmentioning

confidence: 99%

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Divergent Actions of Pyruvate and ATP in Glucose-mediated Irinotecan Chemoresistance in Colorectal Cancer

Huang

Pai

2021

Preprint

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Background: Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). The aim of this study was to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Methods: Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of high concentrations of glucose, pyruvate or ATP-encapsulated liposomes. Cell apoptosis was measured by DNA fragmentation and caspase activities, and necroptosis was evaluated by immunoprecipitation of receptor-interacting protein kinase (RIP) 1/3 complex. Cell cycles were assessed by flow cytometric analysis.Results: Human CRC cell lines treated with irinotecan in the presence of high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in the presence of normal glucose. Irinotecan induced apoptosis and necroptosis, both of which were mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it had no effect on necroptosis. In contrast, pyruvate attenuated the RIP1/3-dependent necroptosis via free radical scavenging, without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated irinotecan-induced G0/G1 shift whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere sizes while pyruvate prevented the deformation of spheroid mass. Conclusions: Glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, which might contribute to tumor recurrence.

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Section: Discussionmentioning

confidence: 54%

Section: Xenograft Mouse Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Divergent Actions of Pyruvate and ATP in Glucose-mediated Irinotecan Chemoresistance in Colorectal Cancer

Huang

Pai

2021

Preprint

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“…Shriwas et al have shown that GLUT inhibitor effectively reduced cell proliferation and metabolism in human lung and cervical cancer cells (Shriwas et al, 2021). A recent study found that overexpression of GLUT is related to 5-fluorouracil resistance, and inhibition of GLUT significantly improved the outcome of treatment in colorectal cancer (Chang et al, 2021). SLT7A11 overexpression in colon cancer cells has been shown to be vulnerable to GLUT inhibitors, which could be induced by mutation of tumor suppressor genes, eg BAP1 or KEAP1 (Zhang et al, 2019;Zhang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Efﬁcacy of glucose transporter inhibitors for the treatment of ERRα-overexpressed colorectal cancer

Zhao¹,

Zhu

2022

Acta Biochim Pol

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Background: Colorectal cancer is the most-incidence associated extremely high mortality rate worldwide. The overexpression of estrogen-related receptor α (ERRα) is contributing to a poor prognosis. Obtaining a better understanding of the mechanisms of ERRα in colorectal cancer is important for developing cancer therapies. Methods: Western blotting and qRT-PCR were used to determine the protein and mRNA levels of ERRα, OUTB1, and solute carrier family 7 member 11 (SLC7A11) in HCT-116 cells. Short hairpin RNA (shRNA) was used to knockdown ERRα in HCT-116 cells. The level of reactive oxygen species (ROS), the nicotinamide adenine dinucleotide phosphate NADP+/NADPH, and the oxidized glutathione (GSSG)/reduced glutathione (GSH) ratio were measured by HPLC-MS to determine the redox state in HCT-116 cells. Lastly, tumor xenograft experiments were carried out to determine the effect of glucose transporter (GLUT) inhibitor. Results: Knockdown of ERRα decreased the expression of OTUB1 and SLC7A11 in HCT-116 cells. SLC7A11 overexpression induced NADPH-dependent redox system collapse. Aberrant expression of ERRα significantly reduced NADPH level and resulted in collapse of the redox system under glucose deprivation. Furthermore, ERR overexpression of ERRα sensitized cancer cells to inhibition of GLUTs. Treatment with GLUT inhibitor significantly reduced tumor volume after 6 weeks of tumor xenograft experiment. Our study demonstrates that the over-expression of ERRα causes redox system collapses via regulating the expressions of OUTB1 and SLC7A11. Conclusion: Up-regulation of SLC7A11 mediates the disruption of cell metabolism and the balance of redox state in colorectal cancer. Additionally, the GLUT inhibitor significantly reduces colorectal tumor volume, suggesting that the GLUT inhibitor could serve as a potential therapy for colorectal treatment.

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“…Early studies in the irinotecan chemoresistance have focused on genetic changes associated with drug metabolism and efflux [7,8]. Accumulating evidence indicates that an altered cellular bioenergetic status causes resistance to cell death and tumor hyperproliferation [9,10], suggesting that metabolic changes could also be involved in tumor chemoresistance. Normal cells rely on oxidative phosphorylation (OXPHOS) to produce energy for fundamental cellular functions.…”

Section: Introductionmentioning

confidence: 99%

Glucose Conferred Irinotecan Chemoresistance through Divergent Actions of Pyruvate and ATP in Cell Death and Proliferation of Colorectal Cancer

Huang

Pai

2022

Oncology

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Altered glucose metabolism is associated with chemoresistance in colorectal cancer (CRC). This study aimed to illustrate the molecular mechanisms of glucose-mediated chemoresistance against irinotecan, a topoisomerase I inhibitor, focusing on the distinct roles of metabolites such as pyruvate and ATP in modulating cell death and proliferation. Four human CRC cell lines, tumorspheres, and mouse xenograft models were treated with various doses of irinotecan in the presence of high concentrations of glucose, pyruvate, or ATP-encapsulated liposomes. In this study, human CRC cell lines treated with irinotecan in high glucose displayed increased cell viability and larger xenograft tumor sizes in mouse models compared to those treated in normal glucose concentrations. Irinotecan induced apoptosis and necroptosis, both mitigated by high glucose. Liposomal ATP prevented irinotecan-induced apoptosis, while it did not affect necroptosis. In contrast, pyruvate attenuated the receptor-interacting protein kinase (RIP) 1/3-dependent necroptosis via free radical scavenging without modulating apoptotic levels. Regarding the cell cycle, liposomal ATP aggravated irinotecan-induced G0/G1 shift, whereas pyruvate diminished the G0/G1 shift, showing opposite effects on proliferation. Last, tumorsphere structural damage, an index of solid tumor responsiveness to chemotherapy, was determined. Liposomal ATP increased tumorsphere size while pyruvate prevented the deformation of spheroid mass. In conclusion, glucose metabolites confer tumor chemoresistance via multiple modes of action. Glycolytic pyruvate attenuated irinotecan-induced necroptosis and potentiated drug insensitivity by shifting cells from a proliferative to quiescent state. On the other hand, ATP decreased irinotecan-induced apoptosis and promoted active cell proliferation, contributing to tumor recurrence. Our findings challenged the traditional view of ATP as the main factor for irinotecan chemoresistance and provided novel insights of pyruvate acting as an antioxidant responsible for drug insensitivity, which may shed light to the development of new therapies against recalcitrant cancers.

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Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil

Cited by 20 publications

References 46 publications

Divergent Actions of Pyruvate and ATP in Glucose-mediated Irinotecan Chemoresistance in Colorectal Cancer

Divergent Actions of Pyruvate and ATP in Glucose-mediated Irinotecan Chemoresistance in Colorectal Cancer

Efﬁcacy of glucose transporter inhibitors for the treatment of ERRα-overexpressed colorectal cancer

Glucose Conferred Irinotecan Chemoresistance through Divergent Actions of Pyruvate and ATP in Cell Death and Proliferation of Colorectal Cancer

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