2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

Bauer, Matthias R.; Joerger, A.C.; Fersht, Alan R.

doi:10.1073/pnas.1610421113

Cited by 94 publications

(122 citation statements)

References 69 publications

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“…Despite a large number of studies linking ERS to toxicants, currently, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage and apoptosis [39, 40]. In this study, we demonstrated the relationship between testicular damage and ERS pathways in response to busulfan.…”

Section: Discussionmentioning

confidence: 67%

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Cui

Ren

et al. 2017

Cell Physiol Biochem

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Background/Aims: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. Methods: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. Results: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. Conclusion: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment.

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Section: Discussionmentioning

confidence: 67%

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Cui

Ren

et al. 2017

Cell Physiol Biochem

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“…However, there are now also emerging therapeutics targeting mutant p53. 21,22 There is an urgent need for novel therapies for TP53 mutant tumors.…”

Section: Discussionmentioning

confidence: 99%

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

Meric‐Bernstam

Zheng

Shariati

et al. 2018

JCO Precision Oncology

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Purpose: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. Patients and Methods: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. Results: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). Conclusions: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

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“…There is not a simple explanation for several reasons, including that they may work simultaneously by multiple routes and that there are pleiotropic effects on mutating p53, including both loss and gain of function. An example of multiple routes is a small alkylator that covalently binds to mutant p53 in some cases, stabilizes it, and rescues its activity in some cancer cell lines, but kills other cancer cell lines via a reactive oxygen species (54). Similarly, several small molecules appear to reactivate p53 but, instead, cause cell death by other routes (3).…”

Section: Peptides and Peptide Combinations Selectively Kill Cancer Cementioning

confidence: 99%

Multisite aggregation of p53 and implications for drug rescue

Wang

Fersht

2017

Proc. Natl. Acad. Sci. U.S.A.

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Protein aggregation is involved in many diseases. Often, a unique aggregation-prone sequence polymerizes to form regular fibrils. Many oncogenic mutants of the tumor suppressor p53 rapidly aggregate but form amorphous fibrils. A peptide surrounding Ile254 is proposed to be the aggregation-driving sequence in cells. We identified several different aggregating sites from limited proteolysis of harvested aggregates and effects of mutations on kinetics and products of aggregation. We present a model whereby the amorphous nature of the aggregates results from multisite branching of polymerization after slow unfolding of the protein, which may be a common feature of aggregation of large proteins. Greatly lowering the aggregation propensity of any one single site, including the site of Ile254, by mutation did not inhibit aggregation in vitro because aggregation could still occur via the other sites. Inhibition of an individual site is, accordingly, potentially unable to prevent aggregation in vivo. However, cancer cells are specifically killed by peptides designed to inhibit the Ile254 sequence and further aggregation-driving sequences that we have found. Consistent with our proposed mechanism of aggregation, we found that such peptides did not inhibit aggregation of mutant p53 in vitro. The cytotoxicity was not eliminated by knockdown of p53 in 2D cancer cell cultures. The peptides caused rapid cell death, much faster than usually expected for p53-mediated transcription-dependent apoptosis. There may also be non-p53 targets for those peptides in cancer cells, such as p63, or the peptides may alter other interactions of partly denatured p53 with receptors.amyloid | mechanism | misfolding | disease T he tumor suppressor p53 is inactivated by mutation in a substantial number of tumors (1-3). Some 30-40% of those oncogenic mutants are simply destabilized by mutations in its core domain. Those mutants are temperature-sensitive, having a WT structure at lower temperatures, but melt at close to body temperature or below and rapidly aggregate (4-6). Protein aggregation occurs in many diseases (7-9). The best mechanistically characterized examples involve the polymerization of aggregationprone peptides (10, 11) or small proteins to give well-defined fibrils based on a regular repeat structure (12-18). The fibrillar aggregates have a characteristic cross-β X-ray diffraction pattern and bind such dyes as Congo Red and Thioflavine T (ThT) (16). The kinetics of aggregation usually follow a nucleation-growth mechanism, with very slow nucleation (19-21). WT p53 itself aggregates at body temperature (4-6, 22-24), and the oncogenic destabilized mutants aggregate even faster to give amorphous structures that display the characteristic diffraction pattern and bind those diagnostic dyes (23, 25), although under certain conditions, such as very high pressure, they will generate regular fibrils (23,26). The mechanism of initiation of aggregation of p53 differs from the usually studied examples. Two molecules of the core domain of p53 exten...

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2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

Cited by 94 publications

References 69 publications

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

Multisite aggregation of p53 and implications for drug rescue

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