Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F

Kuganesan, Nishanth; Dlamini, Samkeliso; Tillekeratne, LM Viranga; Taylor, William R.

doi:10.1016/j.jbc.2021.101365

Cited by 46 publications

(39 citation statements)

References 54 publications

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“…However, p21, as an inhibitor of cyclin-dependent kinases (CDKs), can inhibit ferroptosis. Therefore, these observations indicate that modulation of ferroptosis seems to emanate from multiple points within the cell cycle pathway, not in a manner that can be explained by the operation of a linear pathway (44). Our research did not explore whether the use of ferroptosis inducers had any effect on the cell cycle itself.…”

Section: Discussionmentioning

confidence: 80%

CDK4/6i treatment induces ferroptosis via downregulation of SLC7A11 mediated by SP1 for estrogen receptor positive breast cancers.

Cui

et al. 2022

Preprint

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Purpose: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) can significantly extend tumor response in patients with metastatic estrogen receptor–positive (ER+) breast cancer, but intrinsic and acquired resistance is common. Elucidation of the molecular features of CDK4/6i sensitivity and the efficiency of their combination with novel targeted cell death inducers may pave the way toward improving patient outcomes. Experimental Design: Ferroptosis-related characteristics were observed following treatment with the CDK4/6 inhibitor palbociclib. Transcriptomic analyses and functional assays were performed to determine the targets and regulatory mechanism of palbociclib in the ferroptosis pathway in ER+ breast cancer cell lines. A tumor xenograft model was used to study the synergistic antitumor effects of CDK4/6is in combination with ferroptosis inducers. Results: Ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of the CDK4/6 inhibitor palbociclib. Mechanistically, palbociclib downregulates cystine transporter SLC7A11 by inhibiting SP1 binding to the promoter region of SLC7A11. Furthermore, genetic or pharmacological inhibitors of SP1 or SLC7A11 can enhance cell sensitivity to palbociclib and synergistically inhibit ER+ breast cancer cell growth in combination with palbociclib. A syngeneic ER+ mouse mammary tumor model was used to verify that combined inhibition of SLC7A11 or SP1 and CDK4/6 resulted in marked suppression of tumor growth in vivo. Conclusions: Experimentally, ferroptosis represents some of the CDK4/6i-induced cell death response. This study illustrates the potential for targeting SLC7A11 in combination with CDK4/6 inhibitors and supports the investigation of combination therapy in ER+ breast cancer.

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Section: Discussionmentioning

confidence: 80%

CDK4/6i treatment induces ferroptosis via downregulation of SLC7A11 mediated by SP1 for estrogen receptor positive breast cancers.

Cui

et al. 2022

Preprint

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“…For example erastin , it has a large pharmacophore with strict structure–activity-relationship (SAR) requirements, thus rendering its incorporation into an HDAC pharmacophore without affecting HDAC and ferroptosis activities challenging. We have identified and reported a new ferroptotic agent CETZOLE-1 − (Figure E) that has a 4-cyclopentenyl-2-ethynylthiazole scaffold (therefore, referred to as CETZOLEs ). This compound induces ferroptosis but has a simpler structure, making its incorporation into hybrid molecules easier.…”

Section: Resultsmentioning

confidence: 99%

First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

et al. 2022

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HDAC inhibitors are an attractive class of cytotoxic agents for the design of hybrid molecules. Several HDAC hybrids have emerged over the years, but none combines HDAC inhibition with ferroptosis, a combination which is being extensively studied because it leads to enhanced cytotoxicity and attenuated neuronal toxicity. We combined the pharmacophores of SAHA and CETZOLE molecules to design the first-in-class dual mechanism hybrid molecules, which induce ferroptosis and inhibit HDAC proteins. The involvement of both mechanisms in cytotoxicity was confirmed by a series of biological assays. The cytotoxic effects were evaluated in a series of cancer and neuronal cell lines. Analogue HY-1 demonstrated the best cytotoxic profile with GI50 values as low as 20 nM. Although the increase in activity of the hybrids over the combinations is modest in cellular systems, they have the potential advantage of homogeneous spatiotemporal distribution in in vivo systems.

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“…TP53 is a tumor inhibitor involved in controlling cell survival and division under various pressures [ 54 ], such as the metabolism of lipids [ 55 ], polyamines [ 56 ], iron, and ROS production [ 57 ]. Interestingly, many studies have found that TP53 can influence the redox state, thereby modifying the metabolic processes of cells [ 58 ] and promoting ferroptosis in oxidative stress conditions [ 59 ]. In view of these studies, TP53 is an important regulator for ferroptosis after ICH.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Ferroptosis Mechanism of Zhilong Huoxue Tongyu Capsule for the Treatment of Intracerebral Hemorrhage Based on Network Pharmacology and In Vivo Validation

Wang

Ren

Wang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. The purpose of this study is to explore the mechanism of the Zhilong Huoxue Tongyu (ZL) capsule in the treatment of intracerebral hemorrhage (ICH) via targeting ferroptosis based on network pharmacology. Methods. The active ingredients and related key targets of the ZL capsule were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were also performed. Finally, identified targets were validated in an in-vivo model of ICH. Results. A total of 30 active ingredients and 33 intersecting targets were identified through a TCMSP database search. Ingredients-Targets-Pathways network was constructed to filter out the key targets according to the degree value. TP53 was selected as the key target. The in-vivo validation studies demonstrated that TP53 was down-regulated and GPX4 was upregulated in rats following ZL capsule treatment. Conclusions. It is concluded that the ZL capsule could alleviate ICH in a muti-target and multi-pathway manner. ZL capsule could alleviate ICH by inhibiting ferroptosis, and TP53 is identified to be the potential target. Further research is needed to clarify the detailed anti-ferroptotic mechanism of the ZL capsule.

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Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F

Cited by 46 publications

References 54 publications

CDK4/6i treatment induces ferroptosis via downregulation of SLC7A11 mediated by SP1 for estrogen receptor positive breast cancers.

CDK4/6i treatment induces ferroptosis via downregulation of SLC7A11 mediated by SP1 for estrogen receptor positive breast cancers.

First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

Exploring the Ferroptosis Mechanism of Zhilong Huoxue Tongyu Capsule for the Treatment of Intracerebral Hemorrhage Based on Network Pharmacology and In Vivo Validation

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