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Home Current Topics Anticancer Agent also Boosts Host Responses to Some Pathogens
Anticancer Agent also Boosts Host Responses to Some Pathogens Print E-mail

 

A low-molecular-weight compound that is being developed as an anticancer agent also has promising antimicrobial activities, according to researchers at the Ohio State University (OSU), Columbus.  Rather than attacking microbial pathogens directly, however, AR-12 modulates host cell pathways, turning up their defensive activities against those bacteria, a mechanism that could reduce the potential for resistance to develop. Thus, treating mice with AR-12 after they were infected with Salmonella enterica serovar Typhimurium "caused a modest, but significant prolongation of survival," says Samuel Kulp of OSU, who collaborated with Hao- Chieh Chiu on this project. Details of the research appear in the December 2009 Antimicrobial Agents and Chemotherapy (53:5236-5244).

AR-12 derives from celecoxib, itself an inhibitor of COX-2, which is a key host enzyme involved in inflammatory responses. Unlike celecoxib, however, AR-12 has anticancer activity. For example, Kulp and his collaborators earned that it induces autophagy in breast cancer cells. Drawing on his background in microbiology, Chiu wondered whether this capacity of AR-12 for triggering autophagy, which also plays a role in clearing bacterial pathogens during infections, could be tapped for fending off pathogens. Indeed, AR-12 acts in at least two ways to augment host responses against microbial invaders, according to Chiu and Kulp. First, it inhibits signaling in the host Akt kinase pathway, which interferes with Salmonella- induced upregulation of that pathway. Ordinarily during an infection, elevated activity in that pathway promotes cytoskeletal dynamics that enable the bacteria to proliferate. Second, it stimulates autophagy, including by infected macrophages.

"AR-12 potently induces autophagy and inhibits the intracellular survival of S. enterica in infected macrophages at concentrations and treatment durations that have no cytotoxic effects on the host macrophages themselves," Kulp says. Furthermore, AR-12 suppresses bacterial survival by interfering with proteins that regulate autophagy.

Kulp suspects that AR-12 acts upon other host pathways that make conditions difficult for S. enterica or other pathogens. "Our validation experiments, involving expression of constitutively active Akt1 and siRNA-mediated disruption of autophagy, failed to fully protect bacteria from the effects of AR-12," he says, referring to small interfering (si), double-stranded RNA (siRNA) molecules that help to control gene expression in host cells.

This approach to antimicrobial therapeutics is "very promising," and such efforts should be pursued, says Deborah Hung of Harvard Medical School in Boston, Mass. However, not every effort to identify interference RNA (RNAi) molecules to protect against pathogens is going to lead to useful therapeutics, she adds. Moreover, she urges caution in interpreting these particular results, noting that the drop in bacterial load for salmonellainfected mice is "subtle at best," while the increase in survival among these animals "is small."

Meanwhile, Arno Therapeutics, Inc., in Parsippany, N.J., holds the clinical development rights to AR-12, which can be administered orally. This clinical-stage biopharmaceutical company, which focuses on oncology products, is evaluating AR-12 in phase-I clinical trials involving patients with recurrent solid tumors or lymphoma.

David Holzman