Nat commun: accident! Commonly used tapeworm drug is a broad-spectrum anti-cancer drug!

March 20, 2019 a new study by BIOON / A * star shows that a drug used to treat tapeworm infection can be used to treat a range of cancers More than half of cancer patients have mutations in the tumor suppressor gene p53, which makes p53 a very attractive target for cancer Photo source: many studies of nature communications focus on the direct or indirect recovery of p53 function in mutant cells, but the research team led by chit Fang Cheok of the Institute of molecular and cell biology of a * star adopted a different strategy They didn't try to repair the mutated p53, because this gene mutates in different ways in different cancers They studied the difference between p53 deficient cells and normal cells to explore a new way to treat p53 deficient cancer cells, which Cheok called the loss of targeted p53 (loss of function) The team tested 1600 FDA approved drugs on colon cancer cells carrying normal and mutated p53, and found that the most potent drug to kill p53 deficient cancer cells, rather than p53 normal cancer cells, was niclosamide, a drug used to treat tapeworm infection Subsequent tests showed that niclosamide could also effectively kill other cancer cell lines with p53 mutation Niclosamide affects cells by interfering with mitochondrial production and causing changes in fatty acid metabolism The results show that mitochondrial uncoupling is the basic way for niclosamide to selectively kill p53 mutant cells, but this is not enough to fully explain this phenomenon, because the same degree of mitochondrial uncoupling occurs in normal p53 cells In other words, before the study, scientists didn't know why the drug was more effective in killing p53 mutant cells The researchers examined the metabolism of cells treated with niclosamide and found a significant increase in the amount of a fatty acid called arachidonic acid in cells with p53 mutations Their further analysis found that the uncoupling of mitochondria caused by niclosamide increased the calcium concentration in cells, thus accelerating the production of arachidonic acid The team found that p53 could cope with this change by turning on two genes that degrade arachidonic acid, ALOX5 and aox12b However, these genes will not be activated in the cells mutated by p53, which makes arachidonic acid continuously enriched, thus causing mitochondrial release of cytochrome c, leading to programmed cell death The future work will further explore other drugs that can activate the same signal pathway to treat p53 mutant tumors "We're excited to combine this information in an amazing way." Cheok said To test their model, the researchers knocked out ALOX5 and aox12b in normal p53 cells, and found that these cells were more sensitive to niclosamide, while knocking out ALOX5 and aox12b in p53 deficient cells did not increase their sensitivity to niclosamide Finally, the researchers confirmed that niclosamide was more effective in treating p53 deficient tumors in animals They injected the cultured cells into mice and monitored the growth of tumors after treatment with niclosamide The results showed that niclosamide could reduce the growth rate of p53 deficient tumors by half, but had no effect on p53 normal tumors Based on their findings, the researchers have applied for a patent for this study Because the drug targets p53 defects rather than specific gene mutations, it will be applicable to a wider range of tumors with p53 mutations Niclosamide has been used in human body for decades, and has been listed as an effective, safe and cheap drug by who, which makes it become a life-saving drug that may treat a series of p53 deficient tumors Reference: R Kumar et al Mitochondrial uncoupling reeals a new thermal opportunity for p53 defective cancer, nature communications (2018) Doi: 10.1038/s41467-018-05805-1