CENTER NEWS - THURS., AUGUST 17, 2000

SCIENCE SPOTLIGHT

`Rational' anti-cancer drug could result from study of lab compound antimycin A, says Hockenbery By Michael O'Leary Research By Dr. David Hockenbery could result in a rationally designed anti-cancer drug. -- Photo by Theresa Naujack Could a well-known chemical used in laboratories for 50 years hold the key to combating the most resistant forms of breast, colon, prostate cancers?      Laboratory scientists in the Center's Clinical Research Division think it might. In fact, it could lead to a "rationally" designed anti-cancer drug built molecule-by-molecule, from the ground up.      Researchers commonly use a compound called antimycin A to study cellular metabolism, and the EPA lists it as an ingredient used in a pesticide.      Dr. David Hockenbery's laboratory team, however, found that antimycin A's structure preferentially binds to a well-known cancer gene suspect named Bcl-xL.      Hockenbery, whose laboratory focuses on apoptosis, or programmed cell death, says tumor cells from liver, colon, and myeloma often contain higher than normal levels of Bcl-xL.      "We know that the prognosis for people whose tumors express high levels of Bcl-xL remains poor," he says.      He says the family of Bcl-2 genes, including Bcl-2, Bcl-xL and Bax, regulate programmed cell death. The first two work to block cell death and keep the cell living. The third promotes cell death. Many types of cancer cells overproduce Bcl-2 and Bcl-xL to keep the cell alive and boost resistance to chemotherapy drugs that trigger programmed cell death.      Dr. Shie-Pon Tzung in Hockenbery's lab conducted experiments to find compounds that initiate cell death in cancerous mouse liver cells.      He found that antimycin A selectively killed cells expressing Bcl-xL, with minimal effects on matched cells with lower levels of these proteins.      "We found that the higher the level of Bcl-xL in these cells, the easier they were to kill with antimycin," Hockenbery says. "But at the same time, these cells are the most resistant to multiple chemotherapy drugs. It is almost as if antimycin uncovers an Achille's heel in these cells."      To better understand why antimycin would target highly drug-resistant cells with high Bcl-xL levels, Hockenbery and Tzung asked Dr. Kam Zhang, structural biologist in the Basic Sciences Division, if antimycin might interact with Bcl-2. Did you just have a paper published? Did you attend a scientific meeting? Spread the word in Division Notes! Contact your division administrator or Dr. Barbara Berg, Ext. 2866, to submit your news.        "Based on the crystal structure of Bcl-xL, which we already knew, I built a computer model of Bcl-xL, and showed that antimycin could bind to Bcl-xL at a conserved hydrophobic cleft," Zhang says.      Looking like a cupped hand on one side of the protein, the hydrophobic cleft, as the name implies, repels water, a common characteristic of sites where molecules bind together.      Zhang's model showed that the chemical structure of the antimycin A and the hydrophobic cleft fit nicely together.      Kristine Kim in Zhang's lab then showed that antimycin A and Bcl-xL bind to each other. The final piece of evidence came from a collaboration of Hockenbery's lab with Dr. Joshua Zimmerberg at the National Institute of Child Health and Human Development, showing that antimycin A was a potent inhibitor of Bcl-xL function.      "Because antimycin's ability to kill cells remains proportional to their Bcl-xL levels, it potentially could prove an effective cancer drug for tumors that overproduce these cell survival proteins," Hockenbery says.      "Antimycin also shuts down cellular production of ATP, the energy currency of the cell, by binding to another protein, cytochrome b, which presents a problem because cytochrome b resides in all cells."      The team aims to design a drug based on the chemical and structural features of antimycin A that selectively binds to Bcl-xL and not cytochrome b.      Researchers discovered most current anti-cancer drugs through a systematic "trial and error" process of trying different compounds on cancer cells and selecting those that killed cancer cells to develop into chemotherapy drugs.      Whatever drug Hockenbery's team develops based on antimycin A, it will join the first generation of "rationally" designed cancer drugs, built molecule-by-molecule from the ground up. Such drugs hold great promise of more specifically attacking cancer cells and causing fewer, milder side effects.      [Michael O'Leary is a former science writer for the Center.]