Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance
Abstract
:1. Introduction
2. Glucose Metabolism
3. The Warburg Effect
4. Mechanisms of Cancers’ Drug Resistance
4.1. ABC Transporters
4.1.1. MDR1 Transporter
4.1.2. MRP1 Transporter
4.1.3. BCRP Transporter
4.2. Metabolic Alterations Involved in Drug Resistance in Cancer
4.3. Metabolic Modulation as an Approach to Overcome Drug Resistance
4.4. Self-Delivery of Nanomedicine to Overcome Drug Resistance
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Energetic Profile | Type of Cancer/ Cancer Cell Line | Antimetabolic Drug Effect | Expression and Regulation of MCTs | References |
---|---|---|---|---|
Mainly OXPHOS | Breast (MDA-MB-468) | IACS-010759 induced cell death and inhibited oxygen consumption rate | MCT1 expression at the plasma membrane. MCT4 is expressed on cytoplasm | [26,28] |
Cervical (HeLa) | Metformin and Rotenone promoted anoikis | MCT1 expression > MCT4 expression Hypoxia induced the expression of MCT4 | [31,38,39] | |
Cervical (siHa) | Rotenone decreased cell migration | 2DG and rotenone increased the expression of MCT1 and CD147 | [40,41] | |
Leukemia (THP-1) | Resistant to 2DG and sensitive to oligomycin | MCT4 expression Lactate and VEGF increased the expression of MCT4, but not of MCT1 | [24,25] | |
Lung (A549) | Resistant to 3BP, DCA and 2DG | No changes were observed in MCT1 and MCT4 upon treatment with 3BP, DCA and 2DG | [37] | |
Melanoma (B16F10) | Metformin and Rotenone promoted anoikis | No data | [31] | |
Ovarian (OVCAR-3) | Atovaquone slowed ovarian cancer growth | No data | [42] | |
Mainly Glycolytic | Bladder (5637) | Sensitive to 2DG. 2DG depleted cellular ATP and potentiated the toxicity of conventional drugs | High expression of MCT1, MCT4 and CD147 Knockdown of MCT4 inhibited 5637 cancer cell line proliferation and clonogenic activity | [43] |
Colon (SW480) | Sensitive to 3BP, 2DG and DCA | High expression of MCT1, MCT2 and MCT4 3BP decreased the expression of MCT1and MCT4, but not of MCT2 | [35,44,45,46,47] | |
Glioma (U251) | Sensitive to DCA, 2DG, resveratrol and CHC | High plasma-membrane expression of GLUT1, MCT1, CD147 Silencing of MCT1 decreased the glycolytic phenotype | [23,30,32,33,34,48] | |
Leukemia (NB4) | Sensitive to 2DG and 3BP | High expression of MCT1 and MCT4 | [24,49,50] | |
Lung (NCI-H460) | Sensitive to 3BP, 2DG and DCA | No association was observed between MCT1 and MCT4 expression and treatment effect with 3BP, DCA and 2DG | [37] | |
Melanoma (A375) | Sensitive to 3BP | High expression of MCT1 | [51] | |
Both glycolytic and OXPHOS | Breast (MCF-7) | 2DG, IAA, DCA and CCP and 3BP induced cell death Pre-treatment with 2DG, IAA, DCA and CCCP enhanced PTX and DOX toxicity Lonidamine potentiated the effect of PTX | High plasma-membrane expression of MCT1 and MCT4. 3BP did not alter the expression | [27,29,31,52,53] |
Glioma (SW1088) | Metformin and Rotenone promoted anoikis DCA, 2DG and phenformin led to a decrease in ATP content Resistent to CHC | Low plasma-membrane expression of MCT1, MCT4 and CD147 | [23,32,36] | |
Liver (HepG2) | 2DG, 3BP and DCA induced cell death and potentiated the effect of DOX Phenphormin inhibited proliferation | High expression of MCT1 and MCT4 and lower expression of MCT2 | [54,55,56] |
Metabolism Pathway | Nanoparticle | Advantages | Disadvantages | Future Perspectives | References |
---|---|---|---|---|---|
Mitochondrial respiration | DCA NP PLGA | Control drug delivery system of small drug molecules | Increased DCA in normal cells could lead to serious side effects | Functionalize NPs to specific tissue receptors | [37] |
CDN polymersome NPs | Induce a metabolic shift toward glycolysis Low toxicity of CDNs in healthy mice | Not applicable to glycolytic cells | Apply to other types of cancer | [195] | |
Aerobic glycolysis | 2DG-NPs-PLGA | Control drug-delivery system of small drug molecules | Extremely low loading rate of 2DG into the 2DG-PLGA-NPs | Combination therapy with 2DG-PLGA-NPs and other therapeutic agents | [193] |
Nanoenabled Energy Interrupter | Sensitive to an acidic TME | Preferential inhibition of NPs on melanoma cells | Increase specificity for other tumor types | [200] | |
Aerobic glycolysis and Mitochondrial respiration | Liposome NPs | Acidic TME favorable for the decomposition of NPs | No data | Combination therapy with nanolipossoma and antitumor agents | [196] |
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Cunha, A.; Silva, P.M.A.; Sarmento, B.; Queirós, O. Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance. Pharmaceutics 2023, 15, 2610. https://doi.org/10.3390/pharmaceutics15112610
Cunha A, Silva PMA, Sarmento B, Queirós O. Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance. Pharmaceutics. 2023; 15(11):2610. https://doi.org/10.3390/pharmaceutics15112610
Chicago/Turabian StyleCunha, Andrea, Patrícia M. A. Silva, Bruno Sarmento, and Odília Queirós. 2023. "Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance" Pharmaceutics 15, no. 11: 2610. https://doi.org/10.3390/pharmaceutics15112610