Antimalaria Drug Offers Antitumor Strategies

Abstract

Q uinacrine, an old antimalaria drug given to millions of soldiers during World War II, is garnering new interest as a chemotherapeutic agent that targets two major cancer-promoting pathways — apparently with minimal toxicity to normal cells.Interest in the drug’s mechanism of action has also spawned a search for structural analogues culminating in a new class of compounds, dubbed curaxins, which appear to mimic how quinacrine works. Recent studies in Wafi k El-Deiry’s lab at the University of Pennsylvania with human colorectal and hepatocellular carcinoma show that quinacrine works synergistically with stalwarts of the chemotherapy arsenal as well as the newer targeted therapy sorafenib to delay tumor growth. In particular, El-Deiry noted a set of experiments he and his colleagues published in the Aug. 1, 2011, issue of Cancer Biology and Therapy that showed quinacrine synergized with sorafenib to nearly eliminate Mcl-1, a key oncogenic survival factor and known chemotherapy resistance factor, in HepG2 hepatocellular carcinoma cells. The group also showed that quinacrine administration greatly reduced high Mcl-1 levels in cells treated with adriamycin, 5-fl uorouracil, and gemcitabine, among other agents. The results were impressive enough to El-Deiry to immediately seek approval for a clinical trial combining capecitabine with quinacrine for patients with advanced colorectal cancer. El-Deiry said his group has written the clinical protocol, which the U.S. Food and Drug Administration is reviewing. He pointed out that few options remain when a colon cancer progresses after fi rstand second-line therapy. Furthermore, El-Deiry is disappointed with the lack of affordable options for patients with advanced disease. “Quinacrine has been used for more than 80 years, and there’s a lot of knowledge about it,” he said. “It’s not a very expensive drug. We need other options for our patients, and this one seems feasible.”