Familiar Antibiotic Slows Prostate Cancer Growth

Though Not Fit for Use in Human Disease, Drug Points Toward Targeted Therapy

Prostate tumors are wily foes, embedding themselves in one of the most delicate parts of a man’s anatomy. Most are discovered while they are well within the confines of the prostate gland and can either be left alone or removed by surgery or radiation. The trick is to get them out without damaging nearby nerves and tissues, such as the urethra or bladder. Cancers that have ventured outside the fleshy gland require a subtler approach—blocking testosterone, the hormone that stimulates prostate tumors to proliferate. But hormone therapy carries its own risks (see Research Brief). And it often fails after a year or two as cancer cells evolve the ability to respond to other triggers.

Photo by Graham Ramsay

“People have been looking for chemotherapy agents for prostate cancer for a long time,” said Guo-fu Hu (center), with co-authors Takanori Tsuji (left) and Norie Yoshioka.

Ideally, these metastatic cancers, and even those confined to the prostate, would be controlled by drugs that target a protein critical to the cancer cell’s survival and growth. Yet chemotherapy has been the least-developed approach in the prostate cancer specialist’s arsenal. Part of the problem has been the lack of a good target. Norie Yoshioka, Guo-fu Hu, and colleagues report that they have discovered such a target, angiogenin. They have also identified a drug, the old-line antibiotic neomycin, that effectively blocks it. The findings appeared online Sept. 13 in Proceedings of the National Academy of Sciences.

“A simple antibiotic—neomycin has been known for many years—can have a really dramatic antitumor activity,” said Hu, HMS assistant professor of pathology.

The study is intriguing in several respects, not least for the way it brings together two icons of medicine. Angiogenin made headlines in 1985 as the first angiogenesis-promoting factor, though it has remained something of a mystery. Several years ago, Hu and colleagues showed that the protein travels to the nucleus of endothelial cells, where it turns on a key gene in the making of ribosomes, the protein factories that are critical for cell survival. They also found that neomycin, an antibiotic first identified in 1949 to public acclaim, had the power to keep angiogenin from making this crucial trip, thereby inhibiting angiogenesis.

Not Yet the Cure
This pattern of activity is repeated in prostate cancer cells, Yoshioka, HMS research fellow in pathology, Hu, and colleagues report. What impressed them most about neomycin’s blocking of angiogenin in prostate cancer cells is the effect it had on tumor growth. Prostate cancer cells implanted onto the backs of nude mice typically develop into palpable tumors in 19 days. Mice treated with neomycin presented a very different picture. Seven out of 12 exhibited no tumors by day 19. Six remained tumor-free eight weeks later, when the experiment ended. The other six exhibited tumors that were only 23 percent the size of controls.

This year, 230,000 men will be diagnosed with prostate cancer, most at an early stage, thanks to methods of detection such as PSA. Of these, approximately 20,000 to 30,000 will have metastatic disease—a number large enough to make prostate cancer the second leading cause of cancer deaths, following lung cancer, among men. Neomycin is not likely to be tried even in these advanced patients. Though commonly found in such ointments as Neosporin, neomycin is extremely toxic to the kidneys when used systemically. Nor is it clear that it would have the same prostate tumor–dampening effect in men.

“It’s a bit of a leap to say that it is working gangbusters in mice, and it is going to work in people,” said Philip Kantoff, HMS professor of medicine at the Dana–Farber Cancer Institute, who is not an author on the study. “But it is not as much of a leap to say, ‘Look, yes, angiogenin is an important target, and we have neomycin. We may not get it into people, but there are chemists out there who can try to figure this one out—maybe a less renally toxic version of neomycin that might be as effective at inhibiting tumorigenesis.’”

Though touted by CNN as a wonder protein when it was first discovered, angiogenin has had something of a checkered career. Most angiogenic proteins, such as VEGF and bFGF, double as growth factors. Angiogenin lacked their ability to stimulate cell growth. And it was unclear how effective it was at stimulating angiogenesis. In the 1990s, researchers discovered that it was expressed in a wide variety of cancer cells. The first hint that angiogenin might be playing an important role in prostate cancer came out of the lab of William Sellers, formerly an HMS associate professor of medicine at DFCI. He and his colleagues developed a transgenic mouse that routinely develops prostatic intraepithelial neoplasias (PINs), a precursor to prostate cancer. Angiogenin was the most highly expressed gene in these PINs. Kantoff and colleagues then showed that angiogenin levels were relatively high in the blood of prostate cancer patients and that they increased as disease progressed from PINs to invasive carcinomas.

Knocking on Angiogenin’s Door
Still, most people assumed that the tumor cells were sending the angiogenin to the endothelial cells in order to promote angiogenesis. In 2005, Hu and colleagues used RNA interference (RNAi) to knock down angiogenin expression in cultured tumor cells and then tried stimulating the cells with VEGF and other growth factors. The cells did not respond, suggesting that angiogenin might also be doing something inside cancer cells. Hu knew that angiogenin works in endothelial cells by translocating into the nucleus and turning on the gene for rRNA, an essential step in ribosome synthesis. Might it be doing the same in prostate tumor cells? Hu and Yoshioka, newly arrived from Japan, where she practiced oral surgery, embarked on a series of experiments.

Yoshioka began by measuring levels of angiogenin in a variety of human prostate tumor samples. Like Kantoff, she found that they increased as disease progressed. She also spotted angiogenin in the nucleus of the prostate cancer cells. To see if it was binding the rRNA gene, she blocked angiogenin, first with RNAi and then with neomycin, in cultured prostate tumor cells. In both cases, rRNA expression went down, as did proliferation.

Even with these preliminary in vitro results, neomycin’s ability to stunt and even stop tumor growth in living mice was surprisingly dramatic. “Half of them never developed tumors up to 56 days or more,” Hu said. The antibiotic also had a remarkable effect on angiogenesis. Neomycin-treated mice exhibited 81 percent less blood vessel growth than controls, suggesting the drug delivers a double-whammy—blocking angiogenin’s activity in both tumor and nearby endothelial cells. Looking more closely at the tumor cells, they could see angiogenin piled up in the cytoplasm. There was none in the nucleus, again suggesting that neomycin works by blocking angiogenin’s nuclear transit.

Hu and Yoshioka are currently following up on the neomycin story. They are looking at a related compound, neamine, and plan to test it in the Sellers mice, which develop prostate neoplasias naturally rather than having them transplanted on their backs. They also hope to interest pharmaceutical companies. “I’d like to see some industry or drug company take over and develop derivatives of neomycin and neamine with more potent activity and less toxicity,” Hu said.

—Misia Landau

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