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In Silico Pharmacokinetic Profiling of the Identified Bioactive Metabolites of Pergularia tomentosa L. Latex Extract and In Vitro Cytotoxic Activity via the Induction of Caspase-Dependent Apoptosis with S-Phase Arrest.

ABSTRACT: The in vitro cytotoxic efficacy of plant latex from Pergularia tomentosa L. was studied using five human cancer cell lines: HeLa cells (cervical carcinoma cells), A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma cells), MDA-MB-231 (metastatic mammary adenocarcinoma), and MRC-5 (lung fibroblast cell line) cells. The phytonutrient content of plant latex was identified using the liquid chromatography/mass spectra-quadrupole time of flight (LC/MS-QTOF) technique. In silico studies of polyphenols were carried out to clarify the potential mode of action of the plant latex's constituents. The treatment of different tumor cell lines with different concentrations of plant latex revealed a potent efficacy on the human lung carcinoma cell line (A-549) (IC₅₀ = 3.89 µg/mL) compared with that with vinblastine as a positive control (IC₅₀ = 7.12 µg/mL). The effect of the potent concentration of plant latex on the A-549 cell line induced cell arrest, upregulated the expression of pre-apoptotic markers, and downregulated the expression of antiapoptotic markers. Seven identified polyphenols were selected for the in silico study. A docking assessment using the epidermal growth factor receptor kinase (EGFRk) and eltronib as a positive control showed a higher affinity for the enzyme receptor of the selected polyphenols, except for methyl orsellinate and ginkgotoxin. The ADMET assessment demonstrated the inhibitory effect of the polyphenols on CYP450, except for ouabagenin and xanthyletine. The selected polyphenols obey Lipinski's drug-likeness with no significant toxicity effect. In conclusion, the plant latex of P. tomentosa L. showed cytotoxic activity on the A-549 cell line, and the selected polyphenols showed a promising prodrug agent with a low profile of toxicity in the study.

SUBMITTER: Abouzied AS

PROVIDER: S-EPMC9501251 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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In Silico Pharmacokinetic Profiling of the Identified Bioactive Metabolites of <i>Pergularia tomentosa</i> L. Latex Extract and In Vitro Cytotoxic Activity via the Induction of Caspase-Dependent Apoptosis with S-Phase Arrest.

Abouzied Amr S AS Abd-Rabo Marwa M MM Huwaimel Bader B Almahmoud Suliman A SA Almarshdi Afnan Abdulkareem AA Alharbi Fai Mutaz FM Alenzi Sulafa Salem SS Albsher Bayan Naef BN Alafnan Ahmed A

Pharmaceuticals (Basel, Switzerland) 20220909 9

The in vitro cytotoxic efficacy of plant latex from <i>Pergularia tomentosa</i> L. was studied using five human cancer cell lines: HeLa cells (cervical carcinoma cells), A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma cells), MDA-MB-231 (metastatic mammary adenocarcinoma), and MRC-5 (lung fibroblast cell line) cells. The phytonutrient content of plant latex was identified using the liquid chromatography/mass spectra-quadrupole time of flight (LC/MS-QTOF) technique. In silico studies of poly ...[more]

PMID: 36145353

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Project description:Simple Summary In this study, the anti-tumor activity of Ficus dubia latex extract (FDLE) against HCT-116 and HT-29 human colorectal cancer cell lines in normal and inflammatory conditions was investigated. The results indicated that an inflammation-activated NF-κB increased proliferation-related proteins and decreased apoptosis-related proteins, leading to hyperproliferation of colorectal cancer cell lines. FDLE exhibited remarkable antiproliferative activity in both conditions, however, more effective anti-proliferation was observed due to its more effective regulation of NF-κB inactivation and some proteins related to cell cycle progression and apoptosis induction in inflammatory condition. Our finding may promote the antiproliferative study of FDLE in inflammation-induced colorectal cancer progression. Abstract Colorectal cancer is one of the most diagnosed cancers that is associated with inflammation. Ficus dubia latex is recognized as a remedy with various therapeutic effects in traditional medicine, including anti-inflammatory and antioxidant activity. The present study aims to compare the anti-tumor activity of Ficus dubia latex extract (FDLE) against HCT-116 and HT-29 human colorectal cancer cell lines in normal and inflammatory condition and explore its mechanism of action. FDLE exhibited remarkable antiproliferative activity against HCT-116 and HT-29 colorectal cancer cell lines in both conditions using MTT and colony formation assays and more effective anti-proliferation was observed in inflammatory condition. Mechanistically, FDLE induced cell cycle arrest at G0/G1 phase by down-regulating NF-κB, cyclin D1, CDK4 and up-regulatingp21 in both cell in normal condition. In inflammatory condition, FDLE not only exhibited stronger induction of cell cycle arrest in both cells by down-regulating NF-κB, cyclin D1, CDK4 and down-regulating p21, but also selectively induced apoptosis in HCT-116 cells by down-regulating NF-κB and Bcl-xl and up-regulating Bid, Bak, cleaved caspase-7 and caspase-3 through stronger ability to regulate these proteins. Our results demonstrated that the phytochemical agent in the latex of Ficus dubia could potential be used for treatment and prevention of human colorectal cancer, especially in inflammation-induced hyperproliferation progression.

Project description:BackgroundDillenia suffruticosa root dichloromethane extract (DCM-DS) has been reported to exhibit strong cytotoxicity towards breast cancer cells. The present study was designed to investigate the cell cycle profile, mode of cell death and signalling pathways of DCM-DS-treated human caspase-3 deficient MCF-7 breast cancer cells.MethodsDillenia suffruticosa root was extracted by sequential solvent extraction. The anti-proliferative activity of DCM-DS was determined by using MTT assay. The mode of cell death was evaluated by using inverted light microscope and Annexin-V/PI-flow cytometry analysis. Cell cycle analysis and measurement of intracellular reactive oxygen species (ROS) were performed by using flow cytometry. MCF-7 cells were co-treated with antioxidants α-tocopherol and ascorbic acid to evaluate whether the cell death was mainly due to oxidative stress. GeXP-based multiplex system was employed to investigate the expression of apoptotic, growth and survival genes in MCF-7 cells. Western blot analysis was performed to confirm the expression of the genes.ResultsDCM-DS was cytotoxic to the MCF-7 cells in a time-and dose-dependent manner. The IC50 values of DCM-DS at 24, 48 and 72 hours were 20.3 ± 2.8, 17.8 ± 1.5 and 15.5 ± 0.5 μg/mL, respectively. Cell cycle analysis revealed that DCM-DS induced G0/G1 and G2/M phase cell cycle arrest in MCF-7 cells at low concentration (12.5 and 25 μg/mL) and high concentration (50 μg/mL), respectively. Although Annexin-V/PI-flow cytometry analysis has confirmed that DCM-DS induced apoptosis in MCF-7 cells, the distinct characteristics of apoptosis such as membrane blebbing, chromatin condensation, nuclear fragmentation and formation of apoptotic bodies were not observed under microscope. DCM-DS induced formation of ROS in MCF-7 cells. Nevertheless, co-treatment with antioxidants did not attenuate the cell death at low concentration of DCM-DS. The pro-apoptotic gene JNK was up-regulated whereby anti-apoptotic genes AKT1 and ERK1/2 were down-regulated in a dose-dependent manner. Western blot analysis has confirmed that DCM-DS significantly up-regulated the expression of pro-apoptotic JNK1, pJNK and down-regulated anti-apoptotic AKT1, ERK1 in MCF-7 cells.ConclusionDCM-DS induced cell cycle arrest and apoptosis in MCF-7 cells via multiple signalling pathways. It shows the potential of DCM-DS to be developed to target the cancer cells with mutant caspase-3.

Dataset Information

In Silico Pharmacokinetic Profiling of the Identified Bioactive Metabolites of Pergularia tomentosa L. Latex Extract and In Vitro Cytotoxic Activity via the Induction of Caspase-Dependent Apoptosis with S-Phase Arrest.

Publications

In Silico Pharmacokinetic Profiling of the Identified Bioactive Metabolites of <i>Pergularia tomentosa</i> L. Latex Extract and In Vitro Cytotoxic Activity via the Induction of Caspase-Dependent Apoptosis with S-Phase Arrest.

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