Novel Scopoletin Derivatives Kill Cancer Cells by Inducing Mitochondrial Depolarization and Apoptosis

2020 ◽  
Vol 21 ◽  
Author(s):  
Zhixian Shi ◽  
Li Chen ◽  
Jianbo Sun
Keyword(s):  
Drug Design ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Mitochondrial Depolarization ◽  
Irreversible Inhibitor ◽  
Apoptotic Pathway ◽  
Normal Cells ◽  
Chemical Structures

Background: Natural products and their molecular frameworks have been explored as invaluable sources of inspiration for drug design by means of structural modification, computer aided drug design, and so on. Scopoletin extracting from multiple herbs exhibits potential anticancer activity in vitro and vivo without toxicity towards normal cells. Objective: To obtain new scopoletin derivatives with enhanced anticancer activity, we performed the chemical structure modification and researched the mechanism of anti-tumor activity. Methods: In this study, we take regard scopoletin as lead compound, designed and synthesized a series of scopoletin derivatives via introducing different heterocyclic fragments, and their chemical structures were characterized by NMR spectra (1H NMR and 13C NMR) and HRMS(ESI). The antiproliferative activity of target compounds in four cancer cell lines (MDA-MB-231, MCF-7, HepG2, and A549) were determined by the MTT assay. Compound 11b was treated with Ac-cys under different reaction condition to explore the thiol addition activity of it. The Annexin V/PI and JC-1 staining assay were performed to investigate the anti-tumor mechanism of 11b. Results: Novel compounds 8a-h and 11a-h derivatives of scopoletin were synthesized. Most of target compounds exhibited enhanced antiproliferative activity against different cancer cells and reduced toxicity towards normal cells. In particular, 11b displayed the optimal antitumor ability against breast cancer MDA-MB-231 cells with an IC50 value of 4.46 μM. 11b also cannot react with Ac-cys under the experimental condition. When treated with 11b for 24 h, the total apoptotic cells increased from 10.8% to 79.3%. Besides, 11b induced the depolarization of mitochondrial membrane potential. Conclusion: 11b was more active than other derivatives, indicating that the introduction of thiophene fragment was beneficial for the enhancement of antitumor effect, and it was also not an irreversible inhibitor basing on the result that the α, β-unsaturated ketones of 11b cannot undergo Michael addition reactions with Ac-cys. Furthermore, studies on the pharmacological mechanism showed that 11b induced the mitochondrial depolarization and apoptosis, which indicated 11b killed cancer cells via mitochondrial apoptotic pathway. Therefore, an in-depth research and structure optimization of this compound is warranted.

scholarly journals Evaluation of β-Sitosterol Loaded PLGA and PEG-PLA Nanoparticles for Effective Treatment of Breast Cancer: Preparation, Physicochemical Characterization, and Antitumor Activity

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 232 ◽  
Author(s):  
Moses Andima ◽  
Gabriella Costabile ◽  
Lorenz Isert ◽  
Albert Ndakala ◽  
Solomon Derese ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Size Distribution ◽  
Antiproliferative Activity ◽  
Breast Cancer Cells ◽  
Encapsulation Efficiency ◽  
Plga Nanoparticles

β-Sitosterol (β-Sit) is a dietary phytosterol with demonstrated anticancer activity against a panel of cancers, but its poor solubility in water limits its bioavailability and therapeutic efficacy. In this study, poly(lactide-co-glycolic acid) (PLGA) and block copolymers of poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) were used to encapsulate β-Sit into nanoparticles with the aim of enhancing its in vitro anticancer activity. β-Sitosterol-loaded PLGA and PEG-PLA nanoparticles (β-Sit-PLGA and β-Sit-PEG-PLA) were prepared by using a simple emulsion-solvent evaporation technique. The nanoparticles were characterized for size, particle size distribution, surface charge, and encapsulation efficiency. Their cellular uptake and antiproliferative activity was evaluated against MCF-7 and MDA-MB-231 human breast cancer cells using flow cytometry and MTT assays, respectively. β-Sit-PLGA and β-Sit-PEG-PLA nanoparticles were spherical in shape with average particle sizes of 215.0 ± 29.7 and 240.6 ± 23.3 nm, a zeta potential of −13.8 ± 1.61 and −23.5 ± 0.27 mV, respectively, and with narrow size distribution. The encapsulation efficiency of β-Sit was 62.89 ± 4.66 and 51.83 ± 19.72 % in PLGA and PEG-PLA nanoparticles, respectively. In vitro release in phosphate-buffered saline (PBS) and PBS/with 0.2% Tween 20 showed an initial burst release, followed by a sustained release for 408 h. β-Sit-PLGA nanoparticles were generally stable in a protein-rich medium, whereas β-Sit-PEG-PLA nanoparticles showed a tendency to aggregate. Flow cytometry analysis (FACS) indicated that β-Sit-PLGA nanoparticles were efficiently taken up by the cells in contrast to β-Sit-PEG-PLA nanoparticles. β-Sit-PLGA nanoparticles were therefore selected to evaluate antiproliferative activity. Cell viability was inhibited by up to 80% in a concentration range of 6.64–53.08 μg/mL compared to the untreated cells. Taken together, encapsulation of β-Sitosterol in PLGA nanoparticles is a promising strategy to enhance its anticancer activity against breast cancer cells.

N,N-Ru(ii)-p-cymene-poly(N-vinylpyrrolidone) surface functionalized gold nanoparticles: from organoruthenium complex to nanomaterial for antiproliferative activity

2021 ◽  
Author(s):  
Durairaj Gopalakrishnan ◽  
S. Saravanan ◽  
Ronald Merckx ◽  
Arumugam Madan Kumar ◽  
Themmila Khamrang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gold Nanoparticles ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
First Report ◽  
Functionalized Gold Nanoparticles ◽  
Arene Complex ◽  
Colorectal Cancer Cells

The first report of a Ru(arene)metallopolymer–gold nanoconjugate to enhance the in vitro anticancer activity of Ru–arene complex in colorectal cancer cells.

scholarly journals In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 41
Author(s):  
Estefanía Burgos-Morón ◽  
Nuria Pastor ◽  
Manuel Luis Orta ◽  
Julio José Jiménez-Alonso ◽  
Carlos Palo-Nieto ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Excision Repair ◽  
Leukemia Cell ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Leukemia Cell Lines ◽  
Bulky Dna Adducts ◽  
Inhibition Of Glycolysis

We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore the possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (comet assay). Cells deficient in the nucleotide excision repair (NER) pathway were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. Combinations of AzGalp with oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also showed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

scholarly journals In Vitro Anticancer Activity and Mechanism of Action of an Aziridinyl Galactopyranoside

2018 ◽  
Author(s):  
Estefanía Burgos-Morón ◽  
Nuria Pastor ◽  
Manuel Luis Orta ◽  
Julio José Jiménez-Alonso ◽  
Carlos Palo-Nieto ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Excision Repair ◽  
Leukemia Cell ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Leukemia Cell Lines ◽  
Bulky Dna Adducts ◽  
Inhibition Of Glycolysis

We recently screened a series of new aziridines β-D-galactopyranoside derivatives for selective anticancer activity and identified 2-methyl-2,3-[N-(4-methylbenzenesulfonyl)imino]propyl 2,3-di-O-benzyl-4,6-O-(S)-benzylidene-β-D-galactopyranoside (AzGalp) as the most promising compound. In this article, we explore possible mechanisms involved in the cytotoxicity of this aziridine and evaluate its selective anticancer activity using cancer cells and normal cells from a variety of tissues. Our data show that AzGalp induces DNA damage (detected with the comet assay). Cells deficient in the DNA repair pathway nucleotide excision repair (NER) were hypersensitive to the cytotoxicity of this compound. These results suggest that AzGalp induces bulky DNA adducts, and that cancer cells lacking a functional NER pathway may be particularly vulnerable to the anticancer effects of this aziridine. Several experiments revealed that neither the generation of oxidative stress nor the inhibition of glycolysis played a significant role in the cytotoxicity of AzGalp. The combinations of AzGalp with either oxaliplatin or 5-fluorouracil slightly improved the ability of both anticancer drugs to selectively kill cancer cells. AzGalp also displayed selective cytotoxicity against a panel of malignant cells versus normal cells; the highest selectivity was observed for two acute promyelocytic leukemia cell lines. Additional preclinical studies are necessary to evaluate the anticancer potential of AzGalp.

scholarly journals Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1838
Author(s):  
Naglaa M. Ahmed ◽  
Mahmoud M. Youns ◽  
Moustafa K. Soltan ◽  
Ahmed M. Said
Keyword(s):  
Molecular Modeling ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

scholarly journals Antiproliferative Activity and Potential Mechanism of Marine-Sourced Streptoglutarimide H against Lung Cancer Cells

Marine Drugs ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 79
Author(s):  
Hengju Ge ◽  
Di Zhang ◽  
Muran Shi ◽  
Xiaoyuan Lian ◽  
Zhizhen Zhang
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Lung Cancer Cells ◽  
Potential Mechanism ◽  
Nucleotide Synthesis ◽  
Factor C ◽  
Antiglioma Activity

In 2019, streptoglutarimide H (SGH) was characterized as a new glutarimide from the secondary metabolites produced by a marine-derived actinomycete Streptomyces sp. ZZ741 and shown to have in vitro antiglioma activity. However, the antiproliferative activity and potential mechanism of SGH against lung cancer cells have not yet been characterized. This study demonstrated that SGH significantly inhibited the proliferation of different lung cancer cells. In terms of mechanism of action, SGH downregulated cell cycle- and nucleotide synthesis-related proteins to block cell cycle at G0/G1 phase, reduced the expression levels of glycolytic metabolic enzymes to inhibit glycolysis, and downregulated the important cancer transcription factor c-Myc and the therapeutic target deubiquitinase USP28. Potent anticancer activity and multiple mechanisms indicated SGH to be a novel antitumor compound against lung cancer cells.

scholarly journals Ultrasound-enhanced biosynthesis of uniform ZnO nanorice using Swietenia macrophylla seed extract and its in vitro anticancer activity

2021 ◽  
Vol 10 (1) ◽  
pp. 572-585
Author(s):  
Darren Yi Sern Low ◽  
Camille Keisha Mahendra ◽  
Janarthanan Supramaniam ◽  
Loh Teng Hern Tan ◽  
Learn Han Lee ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Hexagonal Wurtzite Structure ◽  
Colon Cancer Cells ◽  
Swietenia Macrophylla ◽  
Zno Nps ◽  
Human Colon Cancer ◽  
Hct 116

Abstract In this study, ultrasonically driven biosynthesis of zinc oxide nanoparticles (ZnO NPs) using Swietenia macrophylla seed ethyl acetate fraction (SMEAF) has been reported. X-ray powder diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR) analyses confirmed the presence of a pure hexagonal wurtzite structure of ZnO. Field emission scanning electron microscope images revealed the formation of uniquely identifiable uniform rice-shaped biologically synthesized ZnOSMEAF particles. The particle sizes of the biosynthesized NPs ranged from 262 to 311 nm. The underlying mechanisms for the biosynthesis of ZnOSMEAF under ultrasound have been proposed based on FTIR and XRD results. The anticancer activity of the as-prepared ZnOSMEAF was investigated against HCT-116 human colon cancer cell lines via methyl thiazolyl tetrazolium assay. ZnOSMEAF exhibited significant anticancer activity against colon cancer cells with higher potency than ZnO particles prepared using the chemical method and SMEAF alone. Exposure of HCT-116 colon cancer cells to ZnOSMEAF promoted a remarkable reduction in cell viability in all the tested concentrations. This study suggests that green sonochemically induced ZnO NPs using medicinal plant extract could be a potential anticancer agent for biomedical applications.

scholarly journals NBM-HD-1: A Novel Histone Deacetylase Inhibitor with Anticancer Activity

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Wei-Jan Huang ◽  
Yu-Chih Liang ◽  
Shuang-En Chuang ◽  
Li-Ling Chi ◽  
Chi-Yun Lee ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Xenograft Model ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Cell Cycle Regulators ◽  
Anticancer Activities ◽  
Gene Expressions

HDAC inhibitors (HDACis) have been developed as promising anticancer agents in recent years. In this study, we synthesized and characterized a novel HDACi, termed NBM-HD-1. This agent was derived from the semisynthesis of propolin G, isolated from Taiwanese green propolis (TGP), and was shown to be a potent suppressor of tumor cell growth in human breast cancer cells (MCF-7 and MDA-MB-231) and rat glioma cells (C6), with an IC50ranging from 8.5 to 10.3 μM. Western blot demonstrated that levels of p21(Waf1/Cip1), gelsolin, Ac-histone 4, and Ac-tubulin markedly increased after treatment of cancer cells with NBM-HD-1. After NBM-HD-1 treatment for 1–4 h, p-PTEN and p-AKT levels were markedly decreased. Furthermore, we also found the anticancer activities of NBM-HD-1 in regulating cell cycle regulators. Treatment with NBM-HD-1,p21(Waf1/Cip1)gene expression had markedly increased whilecyclin B1andD1gene expressions had markedly decreased. On the other hand, we found that NBM-HD-1 increased the expressions of tumor-suppressor genep53in a dose-dependent manner. Finally, we showed that NBM-HD-1 exhibited potent antitumor activity in a xenograft model. In conclusion, this study demonstrated that this compound, NBM-HD-1, is a novel and potent HDACi with anticancer activityin vitroandin vivo.

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