The metabolism of glucose, the central macronutrient, allows for energy to be harnessed in the form of ATP through the oxidation of its carbon bonds. This process is essential for sustaining all mammalian life. In mammals, the end product can be lactate or, upon full oxidation of glucose via respiration in the mitochondria, CO2. In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases, and lactate is produced, even in the presence of oxygen and fully functioning mitochondria. This process, known as the Warburg Effect.
Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis.
Figure 1. Differences in glycolysis pathways between normal cells and cancer cells. (A) In the presence of oxygen, normal cells produce carbon dioxide up to 38 ATPs per glucose molecule through glycolysis, TCA cycle, and electron transport system. In a hypoxic environment, pyruvates are accumulated without going through the TCA cycle. These accumulated pyruvates in the muscle tissue are converted to lactic acid and only produce 2 ATPs. (B) Cancer cells only use the glycolysis process, regardless of the presence or absence of oxygen; 2 ATPs are produced per glucose molecule and, therefore, compared to normal cells, more glucose is required to obtain energy.
Unlike normal cells, cancer cells require considerable energy to replicate due to their inherent characteristic of abnormally rapid proliferation. The tumor microenvironment (TME), such as hypoxia, results in metabolic changes, including the Warburg effect, in cancer cells. Alterations of the tumor microenvironment due to hypoxia-inducible factor-1 (HIF) initiate transcription programs under hypoxic stress conditions. Other changes include signaling pathways, from oxidative metabolism to reduced metabolism, consumption of glutamine, lipid biosynthesis and drug resistance. All these changes benefit cancer cells. Interfering the Warburg effect is a promising direction for cancer treatment.
Extensive evidence indicated that traditional Chinese medicine (TCM) possesses definite advantages over conventional therapies in terms of fewer side effects, lower toxicity, and less economic burden.
Recent studies indicate that some antineoplastic components from TCM possess regulatory effects on glucose metabolism, and metabolic associated factors and enzymes may become their potential targets.
The detailed regulatory mechanisms are summarized in Table 1.
Modified Si-Jun-Zi Decoction, composed of six Chinese herbal medicines, was reported to exhibit potent antitumor effects on nude mice models of gastric cancer by decreasing the expression levels of LDHA, glutamine synthetase, and phosphocholine cytidylyltransferase (PCYT2) in glycolysis, glutaminolysis, and lipid metabolism.
In conclusion, TCM has its advantages in ameliorating cancer cell glycolysis reprogramming by its polypharmacological actions, further research may lead to the development of natural antitumor drugs based on reshaping cancer cell Warburg effect.
References:
1. Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect. https://www.mdpi.com/1422-0067/22/12/6173/htm
Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy. https://pubmed.ncbi.nlm.nih.gov/34119622/