Lactate dehydrogenase (LDH) is an enzyme in nearly all living cells that enables rapid energy production when cells lack sufficient oxygen, such as in muscles during intense exercise. An LDH inhibitor is a molecule designed to block this enzyme’s function. The development of these inhibitors is driven by the high dependence on LDH activity in certain diseases, especially some cancers. By halting the enzyme, researchers aim to disrupt cellular processes that contribute to disease.
The Function of Lactate Dehydrogenase
The body’s main method for producing energy requires oxygen. When oxygen is scarce, cells switch to a faster method called anaerobic glycolysis, where glucose is broken down into pyruvate. LDH then converts pyruvate into lactate. This conversion is important because it recycles the molecule NAD+, which is needed to continue glycolysis and generate energy quickly. This process allows muscles to function for short periods of intense activity when oxygen demand outpaces supply.
This pathway is relevant to cancer due to the Warburg effect, first observed in the 1920s. This effect describes the tendency of many cancer cells to rely on anaerobic glycolysis for energy, even when oxygen is available. This reprogramming means tumor cells consume large amounts of glucose and produce significant lactate. Their reliance on this pathway makes them dependent on the LDH enzyme, distinguishing them from healthy cells and making LDH a target for therapy.
Mechanism of LDH Inhibition
An LDH inhibitor’s action can be compared to a lock and key. The LDH enzyme is the lock, with a specifically shaped active site that accepts its target molecule, pyruvate, as the key. An inhibitor prevents this key from working, which halts the enzyme’s activity.
There are two main types of inhibitors. A competitive inhibitor resembles the shape of pyruvate and competes for the enzyme’s active site. By binding to this site, it physically blocks pyruvate and prevents the reaction. The effectiveness of a competitive inhibitor can be overcome by a high concentration of the substrate.
A non-competitive inhibitor binds to a location on the enzyme other than the active site, known as an allosteric site. This binding changes the enzyme’s overall shape, which alters the active site so the substrate no longer fits. Because the inhibitor is not directly competing with the substrate, its effect cannot be reversed by increasing the substrate’s concentration.
Therapeutic Potential in Disease Treatment
The primary application for LDH inhibitors is in cancer treatment. Since many tumor cells rely on the Warburg effect, inhibiting LDH disrupts their metabolism. Blocking LDH prevents the conversion of pyruvate to lactate, leading to two main consequences for the cancer cell. First, it halts the regeneration of NAD+, cutting off the cell’s energy supply. Second, it causes a buildup of pyruvate, which can trigger programmed cell death (apoptosis). This strategy is being investigated for cancers like pancreatic, lung, and breast cancer.
Beyond cancer, LDH inhibitors show potential in other areas, such as treating malaria. The malaria parasite, Plasmodium falciparum, is almost entirely dependent on anaerobic glycolysis for survival, making its LDH enzyme a target. Inhibiting it could selectively eliminate the parasite. Research also suggests a role for LDH in some inflammatory conditions where elevated activity contributes to tissue damage. Using inhibitors to modulate this activity could be an approach to reduce inflammation.
Development of LDH Inhibitor Drugs
The search for effective LDH inhibitor drugs has faced challenges. Early examples included oxamate, which mimics pyruvate but struggles to cross cell membranes, limiting its use. Another was gossypol, a natural compound from the cottonseed plant. Gossypol is a potent but non-selective inhibitor, and its use was hampered by toxicity and off-target effects.
Modern drug development uses techniques like high-throughput screening and computational modeling to design safer inhibitors. A main challenge is achieving selectivity between the two LDH subunits, LDHA and LDHB. In many cancers, the LDHA isoform is overexpressed and is the target. However, LDHA and LDHB are structurally similar, making it difficult to design a drug that blocks one without affecting the other. Since LDHB is common in heart tissue, non-selective inhibition could cause side effects.
The development process for any new drug moves from laboratory discovery through preclinical and clinical trials to establish safety and efficacy. While some LDH inhibitors have been tested in early-phase clinical trials, none are approved for widespread use. The goal is to create inhibitors that are specific for the target isoform, have good cell permeability, and maintain a strong safety profile.