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Updated: Jul 18, 2026
Acute Kidney Injury Model Induced by Cisplatin in Adult Zebrafish
Published on: May 15, 2021
Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation
Man Jiang1, Navjotsin Pabla, Robert F Murphy
1Department of Cellular Biology and Anatomy, Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Georgia 30912, USA.
Abstract:
Nutlins, the newly developed small molecule antagonists of MDM2, activate p53 and induce apoptosis in cancer cells, offering a novel strategy of chemotherapy. Recent studies have further suggested synergistic effects of nutlins with other chemotherapeutic drugs. However, it is unclear whether nutlins increase or decrease the side effects of these drugs in normal non-malignant cells or tissues. Cisplatin is a widely used chemotherapy drug, which has a major side effect of kidney injury. Here we show that Nutlin-3 protected kidney cells against cisplatin-induced apoptosis. The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment. Moreover, the protective effects were shown in MDM2-, MDM4-, or p53-deficient cells. On the other hand, Nutlin-3 suppressed mitochondrial events of apoptosis during cisplatin incubation, including Bax activation and cytochrome c release. Nutlin-3 attenuated cisplatin-induced oligomerization of Bax and Bak but not their interactions with Bcl-XL. In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca2+, Bim peptide, and recombinant tBid. Importantly, it blocked both Bax and Bak oligomerization under these conditions. Together, the results have uncovered a new pharmacological function of nutlins, i.e. suppression of Bax and Bak, two critical mediators of apoptosis.
Insights
Nutlin-3 protects kidney cells from chemotherapy drug cisplatin by inhibiting apoptosis mediators Bax and Bak. This finding reveals a new function for nutlins beyond p53 activation, suggesting potential in reducing chemotherapy side effects.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- Nutlins, MDM2 antagonists, activate p53 to induce apoptosis in cancer cells, presenting a novel chemotherapy strategy.
- Nutlins may synergize with other chemotherapeutics, but their impact on normal tissue side effects remains unknown.
- Cisplatin, a common chemotherapy, causes kidney injury; understanding protective mechanisms is crucial.
Purpose of the Study:
- To investigate the effect of Nutlin-3 on cisplatin-induced kidney cell apoptosis.
- To elucidate the mechanism by which Nutlin-3 exerts cytoprotective effects against cisplatin.
- To explore a potential new pharmacological role for nutlins in mitigating chemotherapy side effects.
Main Methods:
- Treatment of kidney cells with Nutlin-3 and cisplatin.
- Assessment of apoptosis markers, including p53 regulation, Bax/Bak activation, and cytochrome c release.
- Experiments in p53-deficient cells and isolated mitochondria to confirm mechanism.
Main Results:
- Nutlin-3 protected kidney cells against cisplatin-induced apoptosis, independent of p53.
- Nutlin-3 suppressed mitochondrial apoptosis pathways, including Bax and Bak oligomerization and cytochrome c release.
- Nutlin-3 inhibited apoptosis in various cellular contexts and isolated mitochondria, demonstrating a direct effect on Bax/Bak.
Conclusions:
- Nutlin-3 exhibits cytoprotective effects on kidney cells against cisplatin toxicity.
- This protection is mediated by the suppression of Bax and Bak, key apoptosis effectors.
- Nutlins possess a novel pharmacological function in inhibiting apoptosis, independent of p53, with potential therapeutic implications for reducing chemotherapy side effects.
