In a study of preclinical models of colorectal cancer, the researchers identified an underlying mechanism for the activation of p53 by FL118. The agent activates the p53 tumor-suppressor protein largely independent of ataxia telangiectasia mutated (ATM)-dependent DNA damage-mediated p53 activation. ATM-dependent activation of p53 is usually induced by many — if not all — types of DNA-damage drugs, including camptothecin compounds such as irinotecan and topotecan, leading the authors to conclude that FL118’s mechanisms of action are distinct among 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,” said Dr. Li, an Associate Professor of Oncology in the Department of Pharmacology and Therapeutics.
The study showed that FL118 inhibits p53 polyubiquitination and monoubiquitination through the oncogenic Mdm2-MdmX E3 complex, while stimulating Mdm2-mediated MdmX ubiquitination — by changing the target specificity of Mdm2-MdmX E3 complex from p53 to MdmX. This action results in accelerated degradation of MdmX, a p53-negative regulator and oncogenic protein, and activation of p53 signaling and p53-dependent senescence. Importantly, in contrast to p53-dependent senescence induction, in the absence of p53 or in the presence of MdmX overexpression, FL118 promotes p53-independent apoptosis.
“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,” notes Dr. Wang, an Assistant Professor of Oncology in the the Department of Pharmacology and Therapeutics. “We also found that FL118 was particularly effective against MdmX-overexpressing cells.”
The findings support investigation of FL118 as an MdmX-depleting agent in MdmX-targeting personalized cancer therapies. The authors conclude that FL118-based therapy may be beneficial for a subgroup of cancer patients with tumors such as chronic lymphocytic leukemia and melanomas, in which MdmX overexpression confers treatment resistance.
Additional research will be needed to explore how FL118 changes the biochemical properties of the Mdm2-MdmX E3 complex. The team is also investigating the agent’s efficacy in treating pancreatic cancer and ovarian cancer.
Other key findings:
• FL118 uses different antitumor mechanisms in wild-type p53 tumors and p53-deficient tumors. In wild-type p53 tumors, FL118 induces p53/p21-dependent senescence and p53-independent apoptosis, while in p53-deficient tumors, it exclusively induces p53-indpendent apoptosis. Because it more effectively induces cancer cell apoptosis in p53-deficient tumors, FL118 is especially effective against late-stage cancers, which usually lose functional p53 and are resistant to DNA-damage drugs.
• This newly identified dual mechanism of action supports the therapeutic potential of FL118 in targeted, personalized cancer therapeutics for both early-stage (wild-type p53) and late-stage (p53-deficient) cancers.
• Given the fact that normal cells possess wild-type p53 function, FL118-induced p53 activation might explain the favorable toxicology profile of FL118: highly toxic to cancer cells but not so in healthy animal cells, and these different consequences might be mediated through p53 activation.
• Because FL118 promotes MdmX degradation through a unique mechanism involving the ubiquitin-proteasomal pathway, it can be used as an MdmX-targeting agent, as well as an inhibitor of anti-apoptotic proteins.
source : http://www.sciencedaily.com/releases/2014/12/141215094153.htm