Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer
Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2252 |
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| author | Elizabeth Varghese Samson Mathews Samuel Alena Líšková Marek Samec Peter Kubatka Dietrich Büsselberg |
| author_facet | Elizabeth Varghese Samson Mathews Samuel Alena Líšková Marek Samec Peter Kubatka Dietrich Büsselberg |
| author_sort | Elizabeth Varghese |
| collection | DOAJ |
| description | Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC. |
| first_indexed | 2024-03-10T17:35:40Z |
| format | Article |
| id | doaj.art-8b1d591c805d4be796725429bf08d803 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T17:35:40Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8b1d591c805d4be796725429bf08d8032023-11-20T09:52:17ZengMDPI AGCancers2072-66942020-08-01128225210.3390/cancers12082252Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast CancerElizabeth Varghese0Samson Mathews Samuel1Alena Líšková2Marek Samec3Peter Kubatka4Dietrich Büsselberg5Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, QatarDepartment of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, QatarDepartment of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, SlovakiaDepartment of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, SlovakiaDepartment of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, SlovakiaDepartment of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, QatarBreast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.https://www.mdpi.com/2072-6694/12/8/2252anticancer drugbreast cancercancerchemoresistanceglucose metabolismresistance |
| spellingShingle | Elizabeth Varghese Samson Mathews Samuel Alena Líšková Marek Samec Peter Kubatka Dietrich Büsselberg Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer Cancers anticancer drug breast cancer cancer chemoresistance glucose metabolism resistance |
| title | Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer |
| title_full | Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer |
| title_fullStr | Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer |
| title_full_unstemmed | Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer |
| title_short | Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer |
| title_sort | targeting glucose metabolism to overcome resistance to anticancer chemotherapy in breast cancer |
| topic | anticancer drug breast cancer cancer chemoresistance glucose metabolism resistance |
| url | https://www.mdpi.com/2072-6694/12/8/2252 |
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