Veterans Affairs

Lactate trapping complex as a cancer diagnostic and tumor cell killer

Tumoricidal compositions which are less harmful to cells having mitochondria with the capacity to shuttle pyruvate than the subset of cancer cells that exclusively utilize glycolysis

Medical & Biotechnology

l-lactate (white) binds (yellow) to PDLA oligomers (light green).

In 1931, Otto Warburg was awarded the Nobel Prize in medicine for demonstrating glycolysis as the primary anaerobic glucose metabolism within cancer cells. Unfortunately, to date, a universal therapy has not emerged from his work. Since that time, it has become apparent that not all cancer cells utilize glycolysis to produce ATP – some utilize oxidative phosphorylation to generate energy. More specifically, those cells in the interior of a tumor where the oxygen tension is lowest and the environment more acidotic tend to utilize glycolysis while those cells in the periphery where oxygen tension is higher tend to utilize oxidative phosphorylation.

Mechanistically, glycolysis generates protons that need to be transported out of the cell to avoid acid build up and many of the hydrogen ions that are transported out are accompanied by lactate to maintain electrical neutrality. Thus, decreasing the intracellular lactate concentration may cause cell death from unchecked acidosis. The intracellular pHs of the interior and exterior tumor cells are similar but the extracellular fluid surrounding the inner cells is orders of magnitude more acidic. It has been shown that a lactate shuttle exists between inner and outer cells where lactate is converted to pyruvate in the outer cells and then metabolized by oxidative phosphorylation to produce ATP to sustain cancer cells.

But, the explanation of which tumor cells utilize glycolysis is more complex than oxygen availability. Rapid rates of energy production require the expedient but inefficient fermentation of glucose if there are insufficient or functionally abnormal mitochondria to process glucose through oxidative phosphorylation. In addition to the metabolic effects of lactate in glycolysis, lactate has also been shown to contribute to tumor cell invasion and increased cell motility.

Based on the above, Department of Veterans Affairs researchers have proposed and tested methods and complexes for trapping l-lactate in or near a tumor cell by contacting it with, and thereby binding with, an isolated polymer of D-lactic acid (PDLA). PDLA forms a stereocomplex with l-lactate in solution, in vitro, or in vivo, and experiments with human chronic lymphocytic leukemia cells support this. Those cancer cells that utilize transport of lactate to maintain electrical neutrality may cease to multiply or die because of lactate trapping, and those cancer cells that benefit from utilization of extracellular lactate may be impaired. Intracellular trapping of lactate may produce different physiology than inhibition of LDH because the cell loses the option of shuttling pyruvate to an alternative pathway to produce an anion.

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