Photo by Cameron Wells,
Walter and Eliza Hall
Institute of Medical Research
Research published in Cell Reports helps explain how the anticancer agent Nutlin3a fights lymphoma and other hematologic malignancies.
Nutlin3a is known to activate the tumor suppressor p53, but it hasn’t been clear exactly which p53 target genes are essential for the drug’s therapeutic activity.
The new research revealed that PUMA-mediated apoptosis—not p21-mediated cell-cycle arrest or senescence—is responsible for Nutlin3a’s therapeutic activity in lymphoid malignancies.
“By understanding how nutlins are killing cancer cells, we can begin to formulate their best possible use, including choosing the best partner drugs to combine the nutlins with,” said study author Andreas Strasser, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
With this study, Dr Strasser and his colleagues first found that Nutlin3a activates p53 target gene expression and causes cell-cycle arrest and apoptosis in non-transformed mouse lymphoid cells in vitro.
The team then showed that Nutlin3a-mediated killing of these cells requires PUMA but not p21. In vivo, loss of PUMA protected non-transformed mouse lymphoid cells against Nutlin3a-induced killing. Loss of p21 did not provide the same protection.
Next, the researchers found that malignant Eµ-Myc lymphoma cells were much more sensitive to Nutlin3a than were non-transformed lymphoid cells. In vitro experiments with Eµ-Myc lymphoma cells showed that Nutlin3a promotes p53 accumulation and downstream effector pathway activation.
As in previous experiments, PUMA (not p21) proved critical for Nutlin3a-induced killing of Eµ-Myc lymphoma cells in vitro. And loss of PUMA (but not p21) impaired the regression of Eµ-Myc lymphomas induced by Nutlin3a in vivo.
Finally, the researchers found that PUMA contributed to Nutlin3a-induced apoptosis in myeloid leukemia, multiple myeloma, and Burkitt lymphoma cell lines.
The team noted that, because PUMA, a pro-apoptotic BH3-only protein, is critical for the therapeutic impact of Nutlin3a, it may be possible to boost the drug’s efficacy by combining it with BH3 mimetic drugs such as navitoclax or venetoclax.
