Aldose reductase is not news by any stretch; researchers have known since the 1970s that the enzyme plays a key role in diabetic complications.

But for all that, there are no approved aldose reductase inhibitors in the U.S., though there is one on the market in Japan. One inhibitor, Alinea Pharmaceutical Inc.'s Lidorestat (ALN 101) is in Phase II trials, and in 2005, Alinea CEO Paul Marshall told BioWorld Today that the most effective molecules tended to have toxicity problems.

But scientists can (and often must) be optimistic to a fault, and in recent months, research showed that inhibiting aldose reductase also might be clinically useful in both prostate cancer prevention and sepsis treatment, effectively upping the ante for finding something that will work in the clinic.

The work, which was published online in Circulation on Oct. 9, 2006, and in the Oct. 1, 2006, issue of Cancer Research, began with deciphering the detailed structure of the enzyme, which led to unexpected insights about its probable cellular partners in crime.

"Its structure at the active site is very hydrophobic," Satish Srivastava told BioWorld Today. "In fact, lipid aldehydes' - the products of free-radical reactions in cells, which are toxic, as are their metabolites - "are a thousand-fold better substrates for aldose reductase than glucose." Prior to the detailed description of the structure, the working assumption was that aldose reductase did its damage mainly by acting on glucose.

That discovery led to a research program that continues to study aldose reductase in diabetes, but has broadened to include other pathologies. In the paper in Cancer Research, Srivastava and his colleagues published data showing that inhibiting aldose reductase can prevent the formation of colon cancer in mice. In the course of the research, the scientists also found that the enzyme "significantly decreased cytokines and chemokines in the blood, and in the heart," Srivastava said. "So we went looking in a sepsis model."

Their sepsis results in Circulation showed that when mice were injected with an aldose reductase inhibitor (sorbinil, the first aldose reductase inhibitor to flame out in late-stage clinical trials), the heart damage that usually delivers the knockout punch in sepsis could be reduced and survival rates improved.

To gain a better understanding of the mechanisms behind heart protection that inhibiting aldose reductase offers, the researchers also tested the effects of inhibiting aldose reductase in cell culture. Inhibiting the enzyme either pharmacologically or via siRNA, they found that inhibiting aldose reductase prevented the activation of NfkB, and prevented increases in cytokine and chemokine levels in both the blood and the heart. Overall, the results suggested that aldose reductase inhibition works upstream of NfkB rather than inhibiting it directly, possibly by preventing the activation of protein kinase C by lipopolysaccharides.

With the Srivastavas, a penchant for biomedicine has run in the family: Satish Srivastava's son and co-author on the Circulation paper, Deepak Srivastava, is a cardiologist and the director of the Gladstone Institute of Cardiovascular Disease in San Francisco.

"So he is very interested in going ahead and arranging a clinical trial," Srivastava, the elder, said. They are in discussions with industry to get one of the aldose reductase inhibitors, as well as on the lookout for sponsors for a clinical trial.

With more than 30 randomized clinical trials in the past decades leading to just one approved product, treating sepsis has a history of failure that is long and distinguished. If an aldose reductase inhibitor is approved for diabetes, though, it should be easy to repurpose for the treatment of sepsis, because sepsis treatment would be shorter. For sepsis, "clinicians want a window of a few days," Srivastava said. "Because in most cases they are able to kill the microbial infection, but the toxins that are already in the blood keep damaging the heart."