FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX

Ling, Xiang; Xu, Chao; Fan, Chuandong; Zhong, Kai; Li, Fengzhi; Wang, Xinjiang

doi:10.1158/0008-5472.can-14-0683

Cited by 48 publications

(44 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, many novel small molecules with promising activity have been published as MDM2 inhibitors, including a new synthetic approach to obtain stapled peptides, chlorofusin‐inspired class of analogues, fluorescent triazolylpurines, sulfamide and triazole benzodiazepines, oxazoloisoindolinones, dispiroindolinones, a camptothecin analogue (FL118), and an inauhzin analogue, among others. Also, a 2,3′‐bis(1 H ‐indole) scaffold was recently published showing additional hydrophobic interactions with the p53 Val93 as indicated by 2D NMR and modeling studies .…”

Section: Discussionmentioning

confidence: 99%

How To Design a Successful p53–MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures

2015

View full text Add to dashboard Cite

A recent therapeutic strategy in oncology is based on blocking the protein-protein interaction between the murine double minute (MDM) homologues MDM2/X and the tumor-suppressor protein p53. Inhibiting the binding between wild-type (WT) p53 and its negative regulators MDM2 and/or MDMX has become an important target in oncology to restore the antitumor activity of p53, the so-called guardian of our genome. Interestingly, based on the multiple disclosed compound classes and structural analysis of small-molecule-MDM2 adducts, the p53-MDM2 complex is perhaps the best studied and most targeted protein-protein interaction. Several classes of small molecules have been identified as potent, selective, and efficient inhibitors of the p53-MDM2/X interaction, and many co-crystal structures with the protein are available. Herein we review the properties as well as preclinical and clinical studies of these small molecules and peptides, categorized by scaffold type. A particular emphasis is made on crystallographic structures and the observed binding modes of these compounds, including conserved water molecules present.

show abstract

Section: Discussionmentioning

confidence: 99%

How To Design a Successful p53–MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures

2015

View full text Add to dashboard Cite

show abstract

“…Shepherdin is the first example of this type of survivin inhibitors and was rationally designed in 2005 [4]. Shepherdin, a survivin 79 KHSSGCAFL 87 (minimum: 79 KHSSG 83 ) peptidomimetic agent, interrupts heat shock protein (Hsp) 90 interactions with survivin [4,5]. Alternatively, shepherdin was incorporated into cancer cells using adenovirus-mediated expression systems, thus demonstrating a proof of principle for use of agents that disrupt survivin-Hsp90 binding as an anticancer agent [6,7].…”

Section: Inhibitors That Disrupt Survivin Interactions With Its Partnmentioning

confidence: 99%

“…DNA microarray studies showed that FL118 does not inhibit the expression of cIAP1, Bcl-2, Bcl-XL, Bcl-2, Bcl2A1, Bcl-w, Bcl-B, Bcl2L12, Bcl2L13, Bcl-G and Bcl2L15 (unpublished data), indicating additional selectivity of FL118 in its molecular targets. Furthermore, FL118 also inhibits MdmX/Mdm4 [79], a critical oncogenic protein involved in p53 pathway, and ERCC6 [80], a critical regulator in DNA repair. Importantly, while FL118 downregulation of MdmX induced senescence in cancer cells with wild type p53, FL118 exhibits even higher efficacy to inhibit cell growth and induce apoptosis in cancer cells without functional p53 (mutated or null) [79].…”

Section: Fl118mentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

Self Cite

195

171

View full text Add to dashboard Cite

Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

show abstract

“…MDMX binds to p53 and is involved in inhibiting p53 transactivation activity, which represses function of p53 and destabilizes the protein in breast cancer cells (14,36). Our data indicated that metformin reduced MDMX level and activated p53 to regulate apoptosis-related proteins.…”

Section: Discussionmentioning

confidence: 70%

The co‑treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells

et al. 2018

View full text Add to dashboard Cite

Abstract. Metformin, a widely used antidiabetic drug, exhibits anticancer effects which are mediated by the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway. However, its use in anticancer therapy combined with other natural products remains unclear. Flavone as the core structure of flavonoids has been demonstrated to induce cell apoptosis without causing serious side effect. Murine double minute X (MDMX) inhibits tumor suppressor gene p53 whose function is associated with the PI3K/AKT pathway. The results presented herein revealed that the combination of metformin and flavone significantly inhibited cell viability, and increased apoptosis of human breast cancer cells compared with metformin or flavone alone. The combination decreased the protein expression of MDMX, activated p53 through the PI3K/AKT signaling pathway, regulated p53 downstream target genes Bcl-2 apoptosis regulator, BCL2 associated X apoptosis regulator and cleaved caspase3, subsequently inducing apoptosis in MDA-MB-231 and MCF-7 breast cancer cells. These results indicated that dietary flavone may potentiate breast cancer cell apoptosis induced by metformin, and PI3K/AKT is involved in regulating MDMX/p53 signaling. This data suggests that dietary supplementary of flavone is a promising strategy for metformin mediated anticancer effects.

show abstract

FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX

Cited by 48 publications

References 46 publications

How To Design a Successful p53–MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures

How To Design a Successful p53–MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

The co‑treatment of metformin with flavone synergistically induces apoptosis through inhibition of PI3K/AKT pathway in breast cancer cells

Contact Info

Product

Resources

About