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Updated: May 20, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Inauhzin and Nutlin3 synergistically activate p53 and suppress tumor growth
Yiwei Zhang1, Qi Zhang, Shelya X Zeng
1Department of Biochemistry and Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
Abstract:
Several proteins have been suggested in promoting tumor formation in numerous human tissues by inactivating the tumor suppressor p53. This has generated interest in the development of small molecules to block these inhibitors of p53 and to regain p53 activity. Recently, we identified a small molecule, Inauhzin, which can inhibit SIRT1 activity and activate p53. SIRT1 is a deacetylase that deacetylates p53 and facilitates Mdm2 mediated p53 destabilization. In this study, we tested if combining Inauhzin with Nutlin-3, an inhibitor of MDM2-p53 binding, might synergistically activate p53 to suppress tumor growth. Indeed, at lower doses, combination of Inauhzin and Nutlin-3 exhibited a synergistic effect on inhibiting cell growth and promoting apoptosis in human colon and lung cancer cell lines in a p53-dependent fashion. Minimal effects were observed with treatment of either compound alone. Using a xenograft tumor model, we also showed a synergistic effect with both compounds. Thus, to fully regain p53 activity, targeting its multiple inhibitory proteins might be a better approach. Our study provides evidence supporting this concept for achieving better therapeutic efficacy in tumors that possess wild type p53.
Insights
Combining Inauhzin and Nutlin-3 synergistically reactivates tumor suppressor p53, inhibiting cancer cell growth and promoting apoptosis. This dual-action approach enhances therapeutic efficacy in wild-type p53 tumors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Tumorigenesis often involves inactivation of the tumor suppressor p53 by various proteins.
- Developing small molecules to block p53 inhibitors and restore p53 activity is a key therapeutic strategy.
- Inauhzin inhibits SIRT1, a deacetylase that promotes p53 destabilization via Mdm2.
Purpose of the Study:
- To investigate the synergistic effect of combining Inauhzin with Nutlin-3 (an MDM2-p53 inhibitor) on p53 activation and tumor suppression.
- To evaluate the efficacy of this combination therapy in human colon and lung cancer cell lines and a xenograft tumor model.
- To determine if targeting multiple p53 inhibitory proteins offers superior therapeutic benefits.
Main Methods:
- Treatment of human colon and lung cancer cell lines with Inauhzin and Nutlin-3, individually and in combination.
- Assessment of cell growth inhibition and apoptosis induction in a p53-dependent manner.
- Evaluation of synergistic effects in a p53 wild-type xenograft tumor model.
Main Results:
- The combination of Inauhzin and Nutlin-3 demonstrated synergistic inhibition of cell growth and promotion of apoptosis in cancer cell lines at lower doses.
- Minimal effects were observed when either compound was used alone.
- Synergistic anti-tumor effects were confirmed in the xenograft model.
Conclusions:
- Targeting multiple proteins that inhibit p53 activity can lead to synergistic therapeutic effects.
- The combination of Inauhzin and Nutlin-3 represents a promising strategy for enhancing p53 activity and suppressing tumor growth in wild-type p53 cancers.
- This approach offers improved therapeutic efficacy compared to single-agent treatments.
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