In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell

Hu, Kuan; Yin, Feng; Yu, Mengyin; Sun, Chengjie; Li, Jingxu; Liang, Yujie; Li, Wenjun; Xie, Ming‐Sheng; Lao, Yuanzhi; Liang, Wei

doi:10.7150/thno.19840

Cited by 24 publications

(18 citation statements)

References 41 publications

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“…It plays a very important role in the regulation of cell cycle checkpoints caused by DNA damage and participates in maintaining genome stability. 48-50 MDMX, as an inhibitor of p53, could cause the ubiquitination and degradation of p53 [51][52][53]. CHK2 could inhibit the activity of MDMX and then rescue the inhibition of p53 53,54.…”

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confidence: 99%

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Chen

Zhou

Guo

et al. 2019

J Cellular Molecular Medi

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We aimed to investigate the biological function of MELK and the therapeutic potential of OTSSP167 in human bladder cancer (BCa). First, we observed overexpression of MELK in BCa cell lines and tissues and found that it was associated with higher tumour stage and tumour grade, which was consistent with transcriptome analysis.High expression of MELK was significantly correlated with poor prognosis in BCa patients, and MELK was found to have a role in the cell cycle, the G1/S transition in mitosis, and DNA repair and replication. Furthermore, BCa cells presented significantly decreased proliferation capacity following silencing of MELK or treatment with OTSSP167 in vitro and in vivo. Functionally, reduction in MELK or treatment of cells with OTSSP167 could induce cell cycle arrest and could suppress migration. In addition, these treatments could activate phosphorylation of ATM and CHK2, which would be accompanied by down-regulated MDMX, cyclin D1, CDK2 and E2F1; however, p53 and p21 would be activated. Opposite results were observed when MELK expression was induced. Overall, MELK was found to be a novel oncogene in BCa that induces cell cycle arrest via the ATM/CHK2/p53 pathway. OTSSP167 displays potent anti-tumour activities, which may provide a new molecule-based strategy for BCa treatment. K E Y W O R D S bladder cancer, cell cycle, MELK, OTSSP167, p53 | 1805 CHEN Et al.

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confidence: 99%

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Chen

Zhou

Guo

et al. 2019

J Cellular Molecular Medi

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“…After proving CIH concept could be successfully translated, we applied this method to construct longer peptides 3S / 3R and FITC‐3S / FITC‐3R (Figure A) to target MDM2, which is a major negative regulator of the tumor suppressor p53 protein and has been reported as a suitable target for constrained peptides . Their thioether tethered counterparts 4S / 4R and FITC‐4S / FITC‐4R were also prepared as control peptides (Figure A).…”

Section: Results and Disscussionmentioning

confidence: 99%

Effects of chiral center on an all‐hydrocarbon tethered peptide

Shi

Geng

et al. 2018

Peptide Science

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Recently, our group reported that a precisely positioned chiral center on a thioether tether could dominate the backbone peptides' secondary structures and modulate the peptides' biophysical properties. Helical peptides constructed with this chirality induced helicity (CIH) method were named as CIH peptide. In this work, we examined the effects of substituting the thioether tether with an all hydrocarbon tether for the biophysical property differences. Two peptide epimers were prepared and showed distinct secondary structures and the R epimer is helical. Comparing with its thioether counterpart, the all‐hydrocarbon R epimer showed slightly higher helical content, modest improved binding affinity with mammal double minute 2 (MDM2), while similar cell permeability and slightly higher membrane toxicity.

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“…Is the inefficacy due to increasing percentage of CSC population in Cal-27, PA-1, and Cal-27 CisR cells? [22,50]. Dysplasia cells (DysMSCTR16) were not affected by ascorbic acid or the amla and ginger extracts, in regard to cell proliferation.…”

Section: Discussionmentioning

confidence: 97%

Correlation of Antioxidant and Antiproliferative Activity of Amla and Ginger

Kulsum¹,

Suresh²,

Mehta

2018

Asian J Pharm Clin Res

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Objective: Our study focused on evaluating the anticancer property of ascorbic acid and aqueous extract of amla and ginger.Methods: Antioxidant capacity of ascorbic acid, aqueous extract of amla, and ginger was obtained by 2,2-diphenyl-1-picrylhydrazyl method and total antioxidant capacity (TAC). Vero cell line, PA-1, Cal-27, Cal-27 CisR, and DysMSCTR16 cell lines were treated with antioxidants to evaluate its antiproliferative property using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Colony and spheroid formation assays were also carried out in the presence of extracts to assess its role in anticancer stem cell activity.Results: Two volumes of amla 5 µl (~0.016 g) and 25 µl (~0.08 g) and ginger 5 µl (~0.02 g) and 25 µl (~0.1 g) showed TAC activity equivalent to 0.25 mM and 2 mM ascorbic acid, respectively. Amla and ascorbic acid showed significant antiproliferative property in normal (Vero) p=0.05, cancer (PA-1, Cal-27) p=0.005, and resistant (Cal-27 CisR) p=0.05 cell lines and ginger extract in Vero and Cal-27 cell lines (p=0.05). In PA-1 and Cal-27 CisR cell line, ginger extract showed proliferative activity (p=0.005). Antioxidants showed no antiproliferative activity in DysMSCTR16 cells. Amla extract and ascorbic acid showed significant inhibitory effect on spheroid (p=0.005) and colony formation capacity (p=0.0005) among dysplastic, cancer, and resistant cell lines. Ginger showed inhibitory effect (p=0.05) only in colony formation capacity. Conclusion:Overall, we found a strong correlation between antioxidant and antiproliferative activity of ascorbic acid, amla, and ginger. Amla and ascorbic acid proved to be effective in controlling cell proliferation and self-renewal properties of cancer cells. However, ginger was found to have selective and less antiproliferative effect in comparison to amla.

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In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell

Cited by 24 publications

References 41 publications

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Effects of chiral center on an all‐hydrocarbon tethered peptide

Correlation of Antioxidant and Antiproliferative Activity of Amla and Ginger

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