A team at Roswell Park Cancer Institute (RPCI) has published the results of a recent study in the Cancer Research journal, where they show that novel anticancer agent FL118 can activate the p53 tumor-suppressor pathway in cancer cells, boosting cell senescence, or aging.
Past research from the same team had shown that FL118 could induce cancer cell death through the inhibition of several cell-survival proteins, including survivin, Mcl-1, XIAP or cIAP2.
In either of these processes FL118 showed a strong antitumor capacity, which opens up the door to personalized targeted therapies in some types of cancer, including colon cancer.
The team used a preclinical model of colorectal cancer to pinpoint the mechanisms responsible for p53 activation by FL118. In the study titled “Novel Mechanism of Action of FL118 Induces p53-Dependent Senescence by Targeting MdmX degradation in Colorectal Cancer Cells”, researchers found that this investigational drug can activate p53 independently of ataxia telangiectasia mutated (ATM)-dependent DNA damage-mediated p53 activation, which is usually stimulated by different types of DNA-damage drugs, such as irinotecan and topotecan (camptothecin compounds). The authors observed that FL118 had a distinct mechanism of action within camptothecin analogues.
“While FL118 is an analogue of irinotecan and topotecan, two FDA-approved cancer drugs that are also based on the naturally occurring compound camptothecin, our findings add further evidence that FL118 has novel mechanisms of action that may make it especially potent against solid tumors and especially effective as a well-tolerated, targeted therapy,” study author Dr. Fengzhi Li, an Associate Professor of Oncology in the Department of Pharmacology and Therapeutics, said in a press release.
The team found that FL118 could inhibit p53 polyubiquitination and monoubiquitination through the oncogenic Mdm2-MdmX E3 complex, and at the same time it was capable of stimulating Mdm2-mediated MdmX ubiquitination.
Furthermore, when p53 was not present, or when MdmX was overexpressed, FL118 could promote p53-independent cell death.
“These unexpected findings open new therapeutic possibilities and support the notion that MdmX depletion is a critical mechanism for activating p53 signaling to control tumor cells,” study author Dr. Xinjiang Wang, an Assistant Professor of Oncology in the Department of Pharmacology and Therapeutics explained in the press release. “We also found that FL118 was particularly effective against MdmX-overexpressing cells.”
