Identification of small molecule inhibitors of telomerase activity through transcriptional regulation of hTERT and calcium induction pathway in human lung adenocarcinoma A549 cells

Rao, Yerra Koteswara; Kao, Te-Yu; Wu, Ming-Fang; Ko, Jiunn‐Liang; Tzeng, Yew‐Min

doi:10.1016/j.bmc.2010.08.021

Cited by 14 publications

(9 citation statements)

References 34 publications

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“…According to previous reports, the exposed hydroxy group of the flavonoid is a functional group that enhances its anticancer potential [5,13,14]. Herein, compounds 6a – 6c , 14a – 14f were screened for their in vitro telomerase inhibitory activity against HeLa human cervical cancer cells via the telomere repeat amplification protocol–polymerase chain reaction (TRAP–PCR) assay, and compound 5c was chosen as a control.…”

Section: Resultsmentioning

confidence: 99%

“…Among them, flavonoids, as naturally occurring polyphenols, are widely distributed in many field plants and exhibit multitudinous biological and pharmacological properties, for instance, antitumor, cytotoxic, anti-inflammatory, antioxidant, cardiovascular and antidiabetic effects. Several studies have demonstrated that flavonoids can treat and prevent cancer by inhibiting telomerase activity and inducing apoptosis [12,13,14,15]. However, few flavonoids compounds have been developed into commercially available drugs due to their relatively weak anticancer potency and the uncertain mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Fan

Wen

et al. 2019

Molecules

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Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Fan

Wen

et al. 2019

Molecules

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“…27 Second, incubation of A549 cells with MICDH for 24 hours caused an obvious increase in the proportion of apoptotic cells compared with incubation with free DFM. 28 The increased induction of apoptosis by MICDH in human lung adenocarcinoma A549 cells, compared with that by free DFM, may be due to the increases of ROS 29 and intracellular Ca 2+ concentration 30 and the decrease of mitochondrial membrane potential. 31 A previous study has shown that DFM can inhibit tumor cell growth via different mechanisms other than those mentioned here.…”

Section: -22mentioning

confidence: 99%

An optimized molecular inclusion complex of diferuloylmethane: enhanced physical properties and biological activity

Tan¹,

Li²,

Wu³

et al. 2012

IJN

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Objective: The purpose of this study was to explore and evaluate the enhanced physical properties and biological activity of a molecular inclusion complex (MICDH) comprising diferuloylmethane (DFM) and hydroxypropyl-β-cyclodextrin. Methods: The preparation conditions of MICDH were optimized using an orthogonal experimental design. The solubility, in vitro release and model fitting, microscopic morphology, molecular structure simulation, anti-lung cancer activity, and action mechanism of MICDH were evaluated. Results: The solubility of DFM was improved 4400-fold upon complexation with hydroxypropyl-β-cyclodextrin. The release rate of DFM was significantly higher from MICDH than from free DFM. MICDH exhibited higher antitumor activity against human lung adenocarcinoma A549 cells than free DFM. More cells were arrested in the S/G2 phase of the cell cycle or were induced to undergo apoptosis when treated with MICDH than when treated with free DFM. Furthermore, increased reactive oxygen species and intracellular calcium ion levels and decreased mitochondrial membrane potential were observed in cells treated with MICDH. Conclusion: MICDH markedly improved the physical properties and antitumor activity of DFM. MICDH may prove to be a preferred alternative to free DFM as a formulation for DFM delivery in lung cancer treatment.

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“…As a special type of RNA nuclear protease, telomerase synthesizes telomeric DNA sequences that provide tandem GT-rich repeats (TTAGGG) to compensate for telomere shortening (5,6). Activated telomerase can be observed in more than 90% of cancer cases and beconsidered to permit tumor cell immortalization and promote cell malignant transformation (7,8).…”

Section: Introductionmentioning

confidence: 99%

Phosphorothioate-modified antisense oligonucleotides against human telomerase reverse transcriptase sensitize cancer cells to radiotherapy

Cao

Chen

et al. 2017

Molecular Medicine Reports

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Emergence of resistance, unavoidable systemic toxicity and unsatisfactory efficacy arethe main obstacles for traditional cancer therapy. Combination with phosphorothioate modified antisense oligonucleotides (PS‑ASODN) against human telomerase reverse transcriptase (hTERT) may enhance the therapeutic effect of irradiation. However, the effect of PS‑ASODN against hTERT on the anti‑tumor effects of irradiation in liver cancer remain unclear. In the current study, Walker 256 cells were transfected with hTERT PS‑ASODN. Cell proliferation and cell viability were measured using the MTT assay and cell senescence was examined by SA‑β‑gal staining. Telomerase activity was determined by telomeric repeat amplification protocol‑polymerase chain reaction‑ELISA. Cell apoptosis was assayed by flow cytometry and DNA damage was determined by the comet assay.The PS‑ASODN was demonstrated to have an inhibitory effect on cell proliferation and accelerated effect on cell senescence by inhibiting telomerase activity. PS‑ASODN promoted the irradiation‑induced inhibition of cell viability and telomerase activity, and irradiation‑induced DNA damage and cell apoptosis via the activation of apoptosis‑associated proteins. Taken together, these results indicated that combined treatment of PS‑ASODN with irradiation significantly enhanced tumor inhibition. Therefore, PS‑ASODN provides an experimental foundation for gene therapy and is proposed for application in clinical treatment of liver cancer combined with radiotherapy.

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Identification of small molecule inhibitors of telomerase activity through transcriptional regulation of hTERT and calcium induction pathway in human lung adenocarcinoma A549 cells

Cited by 14 publications

References 34 publications

Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

An optimized molecular inclusion complex of diferuloylmethane: enhanced physical properties and biological activity

Phosphorothioate-modified antisense oligonucleotides against human telomerase reverse transcriptase sensitize cancer cells to radiotherapy

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