Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC

Li, Xinyang; Wang, De-pu; Lu, Guoqing; Liu, Kai-li; Zhang, Tingjian; Li, Shuai; O, Kamara Mohamed; Xue, Wen-han; Qian, Xin-hua; Meng, Fan‐hao

doi:10.1016/j.jare.2020.07.008

Cited by 16 publications

(8 citation statements)

References 28 publications

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“…Therefore, cells overexpressing TS will be less sensitive to cell cycle arrest by DNA-damaging agents [ 13 ]. Li and colleagues (2020) reported the development of a new TS inhibitor that can inhibit non–small-cell lung cancer growth by upregulating P53 expression [ 69 ]. Moreover, TS inhibition facilitates DNA damage, induces MMP depolarization, and ultimately activates apoptotic signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells

et al. 2021

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Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca 2+ concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.

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Section: Discussionmentioning

confidence: 99%

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells

et al. 2021

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“…These inhibitors induce apoptosis and cause cell cycle arrests by halting deoxythymidine monophosphate, which is responsible for formation of dTTP (a DNA synthesis precursor) [ 22 ]. From the literature, it is reported that 1,3,4-oxadiazole and 1,2,3-triazole derivatives exhibit antiproliferative activity by inhibiting thymidylate synthase [ 23 , 24 , 25 , 26 , 27 , 28 ] ( Figure 1 ). Our research group has been involved in the development of anticancer leads targeting thymidylate synthase.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 1,2,3-Triazole Tethered Thymol-1,3,4-Oxadiazole Derivatives as Anticancer and Antimicrobial Agents

et al. 2021

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A library of 1,2,3-triazole-incorporated thymol-1,3,4-oxadiazole derivatives (6–18) hasbeen synthesized and tested for anticancer and antimicrobial activities. Compounds 7, 8, 9, 10, and 11 exhibited significant antiproliferative activity. Among these active derivatives, compound 2-(4-((5-((2-isopropyl-5-methylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol (9) was the best compound against all three tested cell lines, MCF-7 (IC50 1.1 μM), HCT-116 (IC50 2.6 μM), and HepG2 (IC50 1.4 μM). Compound 9 was found to be better than the standard drugs, doxorubicin and 5-fluorouracil. These compounds showed anticancer activity through thymidylate synthase inhibition as they displayed significant TS inhibitory activity with IC50 in the range 1.95–4.24 μM, whereas the standard drug, Pemetrexed, showed IC50 7.26 μM. The antimicrobial results showed that some of the compounds (6, 7, 9, 16, and 17) exhibited good inhibition on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The molecular docking and simulation studies supported the anticancer and antimicrobial data. It can be concluded that the synthesized 1,2,3-triazole tethered thymol-1,3,4-oxadiazole conjugates have both antiproliferative and antimicrobial potential.

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“…Generally, cell cycle can be divided into three phases, G0/G1 phase, S phase, and G2/M phase according to DNA synthesis [ 25 ]. Flow cytometry was used to analyze the cell cycle change of HUVECs after the cells were treated with GQDs for 24 h. As is showed in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The cell cycle can be divided into three phases, G0/G1 phase, S phase, and G2/M phase according to DNA synthesis [ 25 ]. The EdU proliferation assay revealed that GQDs could inhibit the growth of HUVECs in vitro and RNA sequencing showed differential expression of both periostin and cell cycle-related genes.…”

Section: Discussionmentioning

confidence: 99%

Graphene quantum dots rescue angiogenic retinopathy via blocking STAT3/Periostin/ERK signaling

et al. 2022

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Background Pathological retinal angiogenesis resulting from a variety of ocular diseases including oxygen induced retinopathy, diabetic retinopathy and ocular vein occlusion, is one of the major reasons for vision loss, yet the therapeutic option is limited. Multiple nanoparticles have been reported to alleviate angiogenic retinopathy. However, the adverse effect cannot be ignored due to the relatively large scale. Graphene quantum dots (GQDs) have shown potential in drug delivery and have been proved biocompatible. In this study, Graphene quantum dots are extensively investigated for their application in angiogenic retinopathy therapy. Results We showed that GQDs were biocompatible nanomaterials in vitro and in vivo. The nanoparticles have a dose-dependent inhibitory effect on proliferation, migration, tube formation and sprouting of human umbilical vein endothelial cells (HUVECs). Further data show that GQDs could inhibit pathological retinal neovascularization in an oxygen-induced retinopathy (OIR) model. The data of RNA sequencing suggested that periostin is involved in this process. GQDs inhibit the expression of periostin via STAT3, and further regulated cell cycle-related protein levels through ERK pathway. The signaling pathway was conformed in vivo using OIR mouse model. Conclusions The present study indicated that GQDs could be a biocompatible anti-angiogenic nanomedicine in the treatment of pathological retinal neovascularization via disrupting periostin/ERK pathway and subsequent cell cycle. Graphical Abstract

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Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC

Abstract: Graphical abstract

Cited by 16 publications

References 28 publications

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells

Synthesis and Biological Evaluation of 1,2,3-Triazole Tethered Thymol-1,3,4-Oxadiazole Derivatives as Anticancer and Antimicrobial Agents

Graphene quantum dots rescue angiogenic retinopathy via blocking STAT3/Periostin/ERK signaling

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