Emerging glycolysis targeting and drug discovery from chinese medicine in cancer therapy

Abstract

Molecular-targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells have different metabolic properties from normal cells. Normal cells mostly rely upon the process of mitochondrial oxidative phosphorylation to produce energy whereas cancer cells have developed an altered metabolism that allows them to sustain higher proliferation rates. Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the "Warburg Effect." Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM) is recognized as a valuable source for seeking bioactive anticancer compounds. A great progress has been made to identify active compounds from herbal medicine targeting on glycolysis for cancer treatment. Herein, we provide an overall picture of the current understanding of the molecular targets in the cancer glycolytic pathway and reviewed active compounds from Chinese herbal medicine with the potentials to inhibit the metabolic targets for cancer treatment. Combination of TCM with conventional therapies will provide an attractive strategy for improving clinical outcome in cancer treatment.

Figure 1

Glycolytic pathway and the role of HIF-1α in regulating glycolysis. Glucose was uptaken by increased expression of GLUT in hypoxia cancer cells. Through a series of enzyme reaction, glucose was finally metabolized into lactate and ATP, NAD⁺ was also regenerated by LDH-A for maintaining continuous glycolysis. Lactate was exhausted out of cancer cells by MCT4 and then uptaken by oxygenated cancer cells through MCT1. In the presence of oxygen, lactate is oxidized into pyruvate by LDH-B and pyruvate enters the tricarboxylic acid (TCA) cycle to produce ATP. HIF-1α was the main regulator of some enzymes expression in the glycolytic pathway, including GLUT-1, hexokinase, phosphofructokinase, pyruvate kinase, pyruvate dehydrogenase, LDH-A, and MCT.

Figure 2

The intracellular HIF-1α regulation pathway in normoxia and hypoxia. Under normoxia, HIF-1α will be constituently ubiquitinated and subsequently degraded via proteasomal pathway after recruitment of von Hippel-Lindau protein (pVHL), which depends on the hydroxylation of proline residues on 564 and 402. However, under hypoxia, the praline hydroxylation of HIF-1α will be inhibited, HIF-1α will be translocated into the nucleus and combine with HIF-1β, then activate the transcription of a series of downstream genes including LDH-A, PDK1, GLUT-1, and VEGF. The levels of HIF-1α were also influenced by the PI3K/AKT pathway after stimulation of growth factors such as EGF and IGF.

Figure 3

Antiapoptotic and metabolic roles for mitochondrial hexokinase II (HKII). (Left panel) Specific binding of HKII to the outer mitochondrial membrane (OMM) promotes ATP exchanges through complexes consisting of voltage-dependent anion channel (VDAC) and adenine nucleotide (ANT). The effluxed ATP could directly participate the transition from glucose to glucose-6-phosphate, which accelerates the glycolytic activity. Meanwhile, HKII binding to OMM also antagonizes Bax interaction with mitochondrial contact site, which prevents apoptosis occurrence; (Right panel) HKII unbound resulted in the “close” of VDAC-ANT channel, which induces Bax integration and potential changes between outer and inner mitochondrial membrane, and finally leading to release of cytochrome C and apoptosis-inducing factors (AIF) from mitochondrion.

Figure 4

Chemical structures of glycolytic inhibitors derived from Chinese herbs. (a) Chemicals targeting on HIF-1α; (b) HKII inhibitors; (c) Chemicals targeting on LDH-A.