apoptosis in cancer cells
Preclinical research suggests a new class of small-molecule inhibitors could potentially treat leukemias and lymphomas.
Researchers identified compounds targeting the Mdm2–MdmX RING–RING interaction as a new class of E3 ligase inhibitors.
Experiments showed that these compounds, dubbed MMRis, can induce apoptosis in leukemia and lymphoma cells.
The researchers detailed these experiments in Cell Death and Disease.
“We are excited about the unique activities of these compounds and will continue to focus our research efforts on development of their clinical potential,” said study author Xinjiang Wang, PhD, of Roswell Park Cancer Institute in Buffalo, New York.
“These compounds kill cancer cells. [They don’t] just stop cancer cell growth temporarily. These types of agents offer the promise of therapeutic benefit.”
Dr Wang and his colleagues found that MMRis specifically inhibit Mdm2–MdmX E3 ligase activity toward Mdm2 and p53 substrates.
The team said MMRis have an advantage over p53-activating agents that are currently in use as cancer therapies.
That is because MMRis activate the pro-apoptotic function of the p53 pathway, whereas current p53-activating agents temporarily prevent cancer growth but don’t damage existing cancer cells or prevent cancer growth long-term.
The researchers found that 2 MMRi compounds—MMRi6 and its analog, MMRi64—can disrupt Mdm2–MdmX interactions and activate p53 in vitro.
And MMRi64 selectively induces the apoptotic arm of the p53 pathway in leukemia and lymphoma cells.
The team noted that, unlike Nutlin3a, MMRi64 only induces expression of the pro-apoptotic gene PUMA, with minimal induction of the growth-arresting gene p21. However, combining MMRi64 and Nutlin3a produces a synergistic apoptotic effect.
“This study opens a new area for anticancer drug development,” Dr Wang said. “MMRi compounds also can be used as a tool for better understanding the anti-death mechanisms developed by cancer cells.”
“We are moving the research of MMRi compounds forward using both preclinical models and human cancer cell lines. Our hope is that further development of clinically useful MMRi will eventually provide a new treatment option for cancer patients.”
