Plant compound protects healthy cells from chemotherapy drugs

Most chemotherapy drugs damage the DNA of dividing cells. These include not only cancer cells but also healthy cells such as blood, hair follicles, and cells of the mucous membranes of the stomach and gut. So far, researchers have identified only a few drugs that can directly prevent such adverse side effects on healthy tissues, but it has been unclear whether some of these drugs also protect cancer cells themselves from the effects of chemotherapy. This motivated Dr. Min Li-Weber and her team at the DKFZ to search for new compounds. "Rocaglamide was one of many plant substances that we examined," said study head Li-Weber. "This substance is extracted from herbs and has been used in Chinese medicine for many years as, for example, an anti-inflammatory agent."

To determine whether rocaglamide protects healthy cells from chemotherapy drugs, the researchers treated white blood cells from healthy donors with various chemotherapy drugs while adding various levels of rocaglamide. The result: "The more rocaglamide we used, the more white blood cells survived," reports Li-Weber. By contrast, the substance did not have any impact on the survival rate of the cancer cell lines used in the experiment.

How exactly does rocaglamide work? Could it somehow prevent DNA damage in healthy cells? To pursue these questions, the scientists compared the state of DNA in cells either with or without rocaglamide after adding a chemotherapy drug. "The damage was almost identical," says Michael Becker, first author of the publication. "This means on the one hand that rocaglamide does not directly prevent the effects of chemotherapy drugs. On the other hand, it also means that the compound itself does not cause any DNA damage."

In further tests, the scientists found that rocaglamide inhibits the production of the protein p53. This protein, which is also called a "guardian of the genome," is produced by cells that have undergone DNA damage. When p53 reaches a certain level, it induces "programmed cell death,” making sure that the defective cell dies. "Rocaglamide prevents healthy cells that have had contact with a chemotherapy drug from producing the p53 protein and thus from activating programmed cell death," Becker explains. "Since p53 is absent or defective in the cancer cells of about half of all cancer types, rocaglamide had no impact on the cancer cells in our tests." Patients suffering from tumors that do not produce p53 may therefore benefit from rocaglamide, because in these cases, the substance protects only the healthy cells from the effects of chemotherapy.

However, what are the consequences if cells with damaged DNA do not die promptly? Could they give rise to new cancer cells? "Numerous experiments in other labs have shown that inhibiting p53 for a short time does not cause the cancer risk to rise," Becker reports. “Our next step is to determine whether this also holds true for rocaglamide." Becker already has a hypothesis, which remains to be tested, that might explain why p53 inhibitors do not increase a person’s risk of developing cancer: "They might give cells more time to repair damage to their DNA."

Becker MS, Schmezer P, Breuer R, Haas SF, Essers MA, Krammer PH, Li-Weber M. (2014) The traditional Chinese medical compound Rocaglamide protects nonmalignant primary cells from DNA damage-induced toxicity by inhibition of p53 expression. Cell Death Dis. doi: 10.1038/cddis.2013.528