Targeting Glucose Metabolism to Overcome Resistance to Anticancer Chemotherapy in Breast Cancer

Abstract

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.

The Metabolic Mechanisms of Breast Cancer Metastasis

“…A Phase II clinical trial involving 164 patients was recently showed that in patients with HER2-metastatic breast cancer, addition of indoximod, the Indoleamine 2,3-dioxygenase 1 (IDO1) pathway inhibitor, to taxane did not improve PFS compared with taxane alone ( 300 ). The use of glucose metabolic inhibitors such as 2-deoxy-D-glucose (2-DG) and metformin in combination with chemotherapy has shown encouraging results in combating chemotherapy resistance ( 301 ). One patient with medullary breast cancer metastatic to lung and lymph nodes underwent extensive pretreatment (8 previous systemic treatment options) was reported to have a confirmed partial response (PR) with a duration of 65 days when treated with 45 mg/kg 2-DG every other week ( 298 ).…”

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

“…As principally described in the previous section, the metabolic reprogramming of cancer cells allows the switch from OXPHOS to less efficient aerobic glycolysis, regulated by various molecular events such as the HIF-1 regulatory pathway ( Figure 2 ) [ 11 , 68 ]. Dimerization of both HIF subunits (α and β) initiates the transcription of genes associated with increased glucose uptake and lactate production.…”

Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism

“…Aberrant metabolism and elevated glycolytic rates in cancer cells are linked to various oncogenic processes such as proliferation, evasion of apoptosis, angiogenesis, and reprogramming of the tumor microenvironment [ 148 ]. Metabolomic studies reveal that cancers exhibit diverse metabolic phenotypes [ 148 ].…”

“…Aberrant metabolism and elevated glycolytic rates in cancer cells are linked to various oncogenic processes such as proliferation, evasion of apoptosis, angiogenesis, and reprogramming of the tumor microenvironment [ 148 ]. Metabolomic studies reveal that cancers exhibit diverse metabolic phenotypes [ 148 ]. Malignant tumor cells utilize aerobic glycolysis to meet their increased glucose requirements in support of their rapid growth and proliferation; to this end, they overexpress glucose transporters (e.g., Glut1) [ 33 , 149 , 150 , 151 , 152 ].…”

“…Malignant tumor cells utilize aerobic glycolysis to meet their increased glucose requirements in support of their rapid growth and proliferation; to this end, they overexpress glucose transporters (e.g., Glut1) [ 33 , 149 , 150 , 151 , 152 ]. Predominantly glycolytic tumors are characterized by the altered expression of glycolytic enzymes and transporters; therefore, these proteins represent potential targets in anti-cancer treatment [ 148 ].…”