Research progress on natural small molecule inhibitors based on aerobic glycolysis
Malignant tumors are still an important disease that seriously threatens human life and health. Tumor cells exhibit abnormal energy metabolism characteristics, using glycolysis to provide energy even in an oxygen rich environment. Approximately 50% of ATP in tumor cells is synthesized through aerobic glycolysis. Tumor cells can not only utilize the intermediate products of the glycolysis pathway to provide raw materials for synthetic metabolism, but also the increase in lactate caused by the glycolysis pathway can provide an acidic growth environment for tumor cells, which is conducive to their infiltration and metastasis. The mechanism of glycolysis activity in tumor cells is complex and is caused by a combination of multiple factors, including favorable transmembrane structures for glycolysis, abnormal metabolism of key glycolytic enzymes, abnormal expression of oncogenes and signaling pathways, etc. Adjusting glycolytic enzymes is the most important pathway for enhancing glycolysis activity and overexpression. Studies have shown that glucose transporters (GLUTs) can promote glucose transport on the cell membrane, while pyruvate dehydrogenase kinase (PDK), lactate dehydrogenase A (LDHA), pyruvate kinase (PKM), hexokinase (HK) are key rate limiting enzymes in the glycolysis process, and they are highly expressed in many malignant tumors, such as liver cancer, lung cancer, and breast cancer. In addition, inhibiting aerobic glycolysis can effectively suppress tumor cell proliferation and promote tumor cell apoptosis; By changing the metabolic switches induced by hypoxia and targeting these specific enzymes to reduce the activity of tumor cells, reversing the Warburg effect has become an important pathway for anti-tumor treatment.
Research has shown that all 14 members of the glucose transporter (GLUT) family are capable of transporting hexoses and polyols. GLUT1-5 functions as glucose and/or fructose transporters in various tissues and cell types. The metabolic process of aerobic glycolysis (see Figure 1) indicates that the hypoxic microenvironment in most tumors can induce high expression of GLUT1, thereby increasing the glucose uptake ability of tumor cells. This process is the basis for tumor cells to produce the Warburg effect. Hexokinase (HK) is the first rate limiting enzyme in glycolysis, while phosphofructokinase 1 (PFK1) is the second rate limiting enzyme in glycolysis. Its activity is regulated by phosphofructokinase-2/fructose-2,6-diphosphatase (PFKFB). Acetoacetate kinase (PK) has four isoforms, M1, M2, L, and R, and is the third rate limiting enzyme in glycolysis. PKM2 is widely overexpressed in tumor tissues. And lactate dehydrogenase (LDH) catalyzes the final step in the glycolysis process – the interconversion of lactate and pyruvate. Tumor cells mainly express the lactate dehydrogenase subtype LDHA. Elevated LDHA in tumors not only promotes glycolysis, but also promotes the production of lactate, thereby reshaping the tumor microenvironment. This article summarizes the latest progress and mechanisms of action in the research of the above-mentioned proteins and their natural small molecule targeted inhibitors, providing reference for related field research.

 

Aerobic glycolysis, as a specific energy metabolism characteristic of tumor cells, not only provides energy and material supply for the proliferation of tumor cells, but also provides an acidic growth environment for tumor cells due to the increase in lactate caused by the fermentation pathway, which is conducive to their infiltration and metastasis. This article summarizes the small molecule inhibitors found in existing research that target key enzymes in tumor glycolysis from natural sources, intuitively reflecting their structures and providing new ideas for structural modification, in order to provide inspiration for the more effective development and utilization of anti-tumor active ingredients in natural products, the development of multidrug resistance in reverse tumors, the improvement of conventional chemotherapy efficacy, and the enhancement of tumor sensitivity to chemotherapy drugs.