3-Bromopyruvate Blocks Energy Metabolism and Liver Cancer

Abstract

Building on their earlier work, Johns Hopkins researchers have discovered that an apparently nontoxic cellular "energy blocker" can eradicate large liver tumors grown in rats. Six months to more than a year after treatment was stopped, the rats are still cancer free.While the results are dramatic, clinical trials with the chemical, 3-bromopyruvate, are likely some years away, says the study's leader, Young Ko, Ph.D., assistant professor of radiology and biological chemistry. If tests in the lab continue to be promising, however, the chemical or one like it may become an option for treating advanced liver cancers and perhaps other tumors in people."Liver cancer usually isn't detected in people until it's difficult or impossible to treat, and many other aggressive cancers spread to the liver, so we need more treatment options," says Peter Pedersen, Ph.D., professor of biological chemistry in the Institute for Basic Biomedical Sciences at Johns Hopkins. "The compound Dr. Ko tested in animals targets a fundamental process cancer cells need to survive, can kill big tumors, and appears so far to have little or no effect on normal tissues."In fact, Ko says she hasn't been able to find a toxic dose of the compound, which blocks the two ways cancer cells make energy. In earlier experiments with rabbits with liver cancer, reported in 2002, no obvious toxic effects were seen, either. There is a patent pending on possible cancer applications of the compound.While the details of normal cells' protection are still unclear, the scientists suggest cancer cells well-known appetite for sugar might be behind their demise. Ko, who first studied the compound as a graduate student at Washington State University in 1990 and initiated its study at Hopkins, has shown that it completely blocks cancer cells' conversion of sugar into usable energy, a process necessary to fuel the cells' functions and growth."We believe this is the first time that a drug has blocked both ways cancer cells make energy and are very happy that it seems so effective against advanced liver cancers," says Ko. "Usually researchers don't try to attack advanced cancers because success seems unlikely. But these are the very cancers we must learn to defeat if we are to win the war on cancer."Sugar, or glucose, is brought into cells and converted into useable energy, a molecule called ATP, by either of two processes. Another product of this conversion, a molecule called lactate, is then taken out of the cell by specialized transporters.But because cancer cells use so much more sugar and make so much more lactate than normal cells, the researchers suggest cancer cells may be riddled with more of the "two-way streets" that transport lactate. And because 3-bromopyruvate looks very similar to lactate, it might travel those same roads, sneaking into cancer cells like a Trojan horse, suggests Ko.In her latest experiments, described in the Nov. 5 issue of Biochemical and Biophysical Research Communications and available online now, Ko found that treating rat liver cancer cells with 3-bromopyruvate halted the cells' production of ATP within 30 minutes, and visual evidence of the cells' self-destruction was apparent almost immediately. Four times as much of the compound was necessary to begin decreasing ATP production in normal liver cells.Turning to animal studies, Ko injected rat liver cancer cells into either the abdomen or the upper back of 33 rats. Nineteen of the animals received daily injections of the compound into the tumor site for five days or longer, which caused all of the cancers to disappear within four weeks. The rats otherwise appeared unaffected, although Ko will examine the animals when they are euthanized -- probably for old age. The 14 untreated animals that served as controls were euthanized within 10 days because of their tumors' rapid growth.To be sure that the compound had completely eradicated the tumors in the treated animals, Ko and Pedersen collaborated with radiologist Martin Pomper, M.D., Ph.D., Yuchuan Wang, Ph.D., and James Fox. They used radioactive glucose to take PET scans of four of the rats and found that "hot spots" of high uptake disappeared within a few weeks of treatment. PET scans are commonly used to diagnose or stage cancers in people because of tumors' appetite for glucose.Ko is now studying the compound's effects on human cancer cell lines in the lab, and will begin studying it in animal models of breast cancer shortly. The researchers also are planning to examine the compound's effects in an animal model of an aggressive non-liver cancer that spreads to the liver.The research was funded by the National Cancer Institute and the Johns Hopkins Department of Radiology. Authors on the paper are Ko, Wang, Pomper, Pedersen, Barbara Smith, David Rini, Michael Torbenson and Joanne Hullihen, all of Johns Hopkins.