3-Bromopyruvate (3-BP): An effective metabolic inhibitor
Dayspring Cancer Clinic is one of only a few cancer clinics in the United States currently making available 3-Bromopyruvate (3-BP) to patients with all types of cancer, not just liver cancer. Dayspring has an IRB accepted proposal to make this compound available to patients.
In 1931 a German physician/scientist, Dr. Otto Warburg, Ph.D., received a Nobel prize for proving that all cancer cells use anaerobic metabolism (burn sugar without using oxygen) to produce energy. The problem is that this mechanism is 18 times less efficient than the aerobic (oxygen utilizing) metabolism than normal cells will use. Therefore a cancer cell needs 18 times more sugar than a normal cell to grow and remain metabolically active. The resultant metabolic drain on the host is significant.
In cancer, 3-BP surpasses targeted therapies as targeted therapies are quickly made obsolete by intra-tumoral heterogeneities (too genetically varied for a sustained effect). But 3-BP works on all PET scan positive cancer cells. These cancer cells have a cellular metabolism that can be attacked by a small molecule such as 3-BP. Dr. Peter Pedersen’s lab at Johns Hopkins in Baltimore Maryland has thoroughly investigated 3-BP and then a formulation for 3-BP has been worked out to increase efficacy, decrease toxicity and nuance the delivery to cancer cells.
Patients, scientists, and many others are frequently interested in knowing whether 3-BP is more effective and less toxic to cancer patients than currently approved chemotherapy drugs.1 Certainly, this is the case for experimental animals. In fact, 3-BP is one of the most effective anti-cancer drugs, and in some cases, perhaps the most effective.2 3-BP targets the essential energy production machinery of cancer cells while leaving the same machinery in normal cells preserved. This discovery has been instrumental in propelling a new direction in cancer research focused on selectively targeting the cancer cells’ energy production factories. In fact, Dr. Peter Pedersen’s lab of Johns Hopkins is the pioneer in conceptualizing/inventing this new strategy.
There is two energy (ATP) production factories inside the cell, i.e., glycolysis and mitochondrial oxidative phosphorylation. In normal cells, about 5 percent of the total cellular energy (ATP) production is derived from glycolysis and about 95 percent from mitochondria.3 In cancer cells the energy production by glycolysis is significantly increased (up to 60 percent).4 This dramatic increase in glycolysis in cancer cells results in a significant increase in lactic acid production.
More than 90 percent of cancers exhibit this common metabolic phenotype. This is called the “Warburg Effect”, i.e., a significant increase in glycolysis in cancer cells even in the presence of oxygen. The most frequently used cancer detection method clinically, i.e., Positron Emission Tomography (PET), is based on this metabolic phenotype, i.e., the “Warburg effect”.
Cancer cells that exhibit the “Warburg effect” pump out the produced lactic acid via a monocarboxylate transporter (MCT). The number of these transporters (considered as doors or gates) in cancer cells is much greater than in normal cells.
3-BP, a lactic acid analog, is a small chemical and mimics the lactic acid chemical structure. Therefore, 3-BP mimicking lactic acid can enter as a Trojan horse through the MCT’s into cancer cells. It has little effect on normal cells as these contain very few MCT’s under normal physiological conditions.
Because of 3-BP’s highly reactive nature, it then neutralizes the two cancer energy production factories. Cellular energy (ATP) is depleted very rapidly as 3-BP attacks the two factories at the same time causing the cancer cells to die (by cell membrane rupturing). So when cancer cells are treated with 3-BP the cancer cells rupture and cellular death occur. Normal metabolic cells are unaffected.
1 BMC Research Notes 2013, 6:277 doi:10.1186/1756-0500-6-277
2 J Bioenerg Biomembr. 2012 Feb;44(1):1-6. doi: 10.1007/s10863-012-9425-4.
3 Annual Review of Cell and Developmental BiologyVol. 27: 441-464 (Volume publication date November 2011)
4 The Hexokinase 2 Dependent “Warburg effect” and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for effective therapy with the powerful small molecule 3-bromopyruvate. Prepublication paper June 6, 2014 Paweł Lis, Young H. Ko, Peter L. Pedersen*, Andre Goffeau and Stanisław Ułaszewski.