Altered glycolysis results in drug‑resistant in clinical tumor therapy (Review)

Abstract

Cancer cells undergo metabolic reprogramming, including increased glucose metabolism, fatty acid synthesis and glutamine metabolic rates. These enhancements to three major metabolic pathways are closely associated with glycolysis, which is considered the central component of cancer cell metabolism. Increasing evidence suggests that dysfunctional glycolysis is commonly associated with drug resistance in cancer treatment, and aberrant glycolysis plays a significant role in drug-resistant cancer cells. Studies on the development of drugs targeting these abnormalities have led to improvements in the efficacy of tumor treatment. The present review discusses the changes in glycolysis targets that cause drug resistance in cancer cells, including hexokinase, pyruvate kinase, pyruvate dehydrogenase complex, glucose transporters, and lactate, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies. In addition, the association between increased oxidative phosphorylation and drug resistance is introduced, which is caused by metabolic plasticity. Given that aberrant glycolysis has been identified as a common metabolic feature of drug-resistant tumor cells, targeting glycolysis may be a novel strategy to develop new drugs to benefit patients with drug-resistance.

Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components

“…A growing body of research implies that defective or abnormal glycolysis is frequently linked to drug resistance in cancer treatment [194,195]. Glycolysis dysregulation is caused by abnormal expression of glycolysis-related enzymes, including hexokinase 2 (HK2), phosphoglycerate mutase 1 (PGAM1), pyruvate kinase M2 (PKM2), pyruvate dehydrogenase (PDH) complex, and lactate dehydrogenase (LDH), which contributes to tumorigenesis, tumor growth, and tumor therapeutic resistance [196][197][198][199][200]. Therefore, targeting such enzymes could be novel strategies to overcome cancer chemoresistance (Figure 3).…”

AdipoRon and Pancreatic Ductal Adenocarcinoma: a future perspective in overcoming chemotherapy-induced resistance?

“…Several mitochondrial-related pathways and mechanisms have been associated with chemoresistance, such as apoptosis, autophagy, and metabolic remodeling [77] . In accordance with this latter operation, in both oncogene-ablated and gemcitabine-treated PDAC cells, targeting OXPHOS significantly shrank tumor recurrence [31,32,78] . Since an OXPHOS impairment has also been observed in response to AdipoRon administration [68,69] , it is plausible to imagine a link between the damage that occurred at this organelle and the ability to sensitize PDAC resistant cells to gemcitabine.…”

“…Complex I Metformin, rotenone, phenformin [31] Complex IV Arsenic trioxide [32] OXPHOS Complex V Oligomycin [78] Hexokinase 2-deoxy-D-glucose [79] Pyruvate Dehydrogenase CPI-613 (devimistat) [32] Glycolysis LDH-A N-hydroxyindole-based inhibitors [80,81] rate is strictly dependent on several factors, including genetic signatures and performance status scale [75,76] . Recognizing AdipoRon as a potential candidate in gemcitabine-based therapy may provide additional hopes for advanced PDAC patients.…”

The expression and survival significance of sodium glucose transporters in pancreatic cancer

“…The increased uptake and metabolism of glucose is an important hallmark of cancer [ 3 – 5 ]. PDAC is a remarkably stroma-rich, vascular-poor, hypoperfused tumour, leading to deficient drug delivery, which is the main cause of drug resistance.…”