scholarly journals In-silico activity prediction, structure-based drug design, molecular docking and pharmacokinetic studies of selected quinazoline derivatives for their antiproliferative activity against triple negative breast cancer (MDA-MB231) cell line

2022 ◽  
Vol 46 (1) ◽  
Author(s):  
Sagiru Hamza Abdullahi ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba ◽  
Abdullahi Bello Umar
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Reference Drug ◽  
Validation Parameters ◽  
Quinazoline Derivatives ◽  
Pharmacologically Active ◽  
Mb231 Cell

Abstract Background Cancer is a major health threat especially in unindustrialized nations. It surpasses coronary diseases and takes the number one killer position as a result of different global wide influences. Among many breast cancer substrates, triple-negative breast cancer (TNBC) is particularly devastating because it rapidly metastasize to other parts of the body, with a high risk of earlier recession and mortality. Result In this research work, four (4) quantitative structure activity relationship (QSAR) models were developed using a series of quinazoline derivatives with activities against triple negative breast cancer cell line (MDA-MB231), model 1 was selected due to its statistical fitness with the following validation parameters: R2 = 0.875, Q2 = 0.837, R2 − Q2 = 0.038, Next test set = 5, and R2ext = 0.655. Molecular docking studies was performed for the quinazoline series as well as the reference drug (Gefitinib) and the active site of the epidermal growth factor receptor (EGFR) (pdb id = 3ug2). Eight compounds (6, 10, 13, 16, 17, 18, 19 and 20) were observed to have better docking score docking scores relative to Gefitinib. Compound number nineteen from the training set (pred pIC50 = 5.67, Residual = − 0.04 and MolDock score = − 123.238) was identified as the best compound since it has the best Moldock score and was excellently predicted by the selected model with least residual value, Hence was adopted as template for the design of Ten (10) new novel compounds with better activities and better docking scores. The inhibitive activities of the designed compounds were predicted by the selected model and most of them possess an improved activity relative to the template compound (19). The designed compounds were also redocked on to active pocket of the EGFR receptor and it was observed that they displayed better docking scores compared to the Template and the reference drug (Gefitinib) utilized in the design. Furthermore, the designed compounds were subjected to ADMET and drug-likeness studies using SWISSADME and pkCSM online web tools and they were observed to be pharmacologically active, easily synthesized and do not violate the Lipinski’s rule of five. Conclusion Hence, the designed compounds can be employed as inhibitors of MDA-MB231 cell line after passing through in vivo and in vitro evaluation.

Machine Learning-based Virtual Screening Strategy Reveals Some Natural Compounds As Potential PAK4 Inhibitors In Triple Negative Breast Cancer

2020 ◽  
Vol 18 ◽  
Author(s):  
Opeyemi Iwaloye ◽  
Olusola Olalekan Elekofehinti ◽  
Babatomiwa Kikiowo ◽  
Emmanuel Ayo Oluwarotimi ◽  
Toyin Mary Fadipe
Keyword(s):  
Breast Cancer ◽  
Virtual Screening ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Energy Calculation ◽  
Reference Drug ◽  
Predictive Quality

Background: P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many cancers, especially in the progression of Triple Negative Breast Cancer (TNBC). The present study was aimed at designing some potential drug candidates as PAK4 inhibitors for breast cancer therapy. Objective: This study aimed to finding novel inhibitors of PAK4 from natural compounds using computational approach. Methods: An e-pharmacophore model was developed from docked PAK4-coligand complex and used to screen over a thousand natural compounds downloaded from BIOFACQUIM and NPASS databases to match a minimum of 5 sites for selected (ADDDHRR) hypothesis. The robustness of the virtual screening method was accessed by well-established methods including EF, ROC, BEDROC, AUAC, and the RIE. Compounds with fitness score greater than one were filtered by applying molecular docking (HTVS, SP, XP and Induced fit docking) and ADME prediction. Using Machine learningbased approach QSAR model was generated using Automated QSAR. The computed top model kpls_des_17 (R2= 0.8028, RMSE = 0.4884 and Q2 = 0.7661) was used to predict the pIC50 of the lead compounds. Internal and external validations were accessed to determine the predictive quality of the model. Finally the binding free energy calculation was computed. Results: The robustness/predictive quality of the models were affirmed. The hits had better binding affinity than the reference drug and interacted with key amino acids for PAK4 inhibition. Overall, the present analysis yielded three potential inhibitors that are predicted to bind with PAK4 better than reference drug tamoxifen. The three potent novel inhibitors vitexin, emodin and ziganein recorded IFD score of -621.97 kcal/mol, -616.31 kcal/mol and -614.95 kcal/mol, respectively while showing moderation for ADME properties and inhibition constant. Conclusion: It is expected that the findings reported in this study may provide insight for designing effective and less toxic PAK4 inhibitors for triple negative breast cancer.

scholarly journals Isolation and Establishment of a Highly Proliferative, Cancer Stem Cell-Like, and Naturally Immortalized Triple-Negative Breast Cancer Cell Line, KAIMRC2

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1303
Author(s):  
Rizwan Ali ◽  
Hajar Al Zahrani ◽  
Tlili Barhoumi ◽  
Alshaimaa Alhallaj ◽  
Abdullah Mashhour ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Cancer Cell Line

In vitro studies of a disease are key to any in vivo investigation in understanding the disease and developing new therapy regimens. Immortalized cancer cell lines are the best and easiest model for studying cancer in vitro. Here, we report the establishment of a naturally immortalized highly tumorigenic and triple-negative breast cancer cell line, KAIMRC2. This cell line is derived from a Saudi Arabian female breast cancer patient with invasive ductal carcinoma. Immunocytochemistry showed a significant ratio of the KAIMRC2 cells’ expressing key breast epithelial and cancer stem cells (CSCs) markers, including CD47, CD133, CD49f, CD44, and ALDH-1A1. Gene and protein expression analysis showed overexpression of ABC transporter and AKT-PI3Kinase as well as JAK/STAT signaling pathways. In contrast, the absence of the tumor suppressor genes p53 and p73 may explain their high proliferative index. The mice model also confirmed the tumorigenic potential of the KAIMRC2 cell line, and drug tolerance studies revealed few very potent candidates. Our results confirmed an aggressive phenotype with metastatic potential and cancer stem cell-like characteristics of the KAIMR2 cell line. Furthermore, we have also presented potent small molecule inhibitors, especially Ryuvidine, that can be further developed, alone or in synergy with other potent inhibitors, to target multiple cancer-related pathways.

scholarly journals QSAR, molecular docking studies, ligand-based design and pharmacokinetic analysis on Maternal Embryonic Leucine Zipper Kinase (MELK) inhibitors as potential anti-triple-negative breast cancer (MDA-MB-231 cell line) drug compounds

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Hadiza Abdulrahman Lawal ◽  
Adamu Uzairu ◽  
Sani Uba
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Triple Negative Breast Cancer ◽  
Leucine Zipper ◽  
Triple Negative ◽  
Qsar Model ◽  
Docking Studies ◽  
Model Parameters ◽  
Standard Drug ◽  
Molecular Docking Studies

Abstract Background Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics “drug-likeliness” properties of the new compounds before they could proceed to pre-clinical trials. Results The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of (R2) = 0.6715, (R2adj) = 0.61920, (Q2) = 0.5460 and (R2pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five. Conclusions The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line).

scholarly journals Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3871
Author(s):  
Emma Rodriguez ◽  
Guangsheng Pei ◽  
Sang T. Kim ◽  
Alexis German ◽  
Prema Robinson
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Cell Line ◽  
Pc12 Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Option ◽  
Neuronal Cell ◽  
Receptor Antagonism ◽  
Tnbc Cell

Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in combination with cisplatin may serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. We used a neuronal cell line (PC12) and two TNBC cell lines (Sum 185 and Sum 159) for these studies. We determined that the levels of cells expressing the high-affinity SP-receptor (neurokinin 1 receptor (NK1R)), as determined by flow-cytometry was significantly elevated in response to cisplatin in all three cells. We determined that treatment with aprepitant, an SP-receptor antagonist decreased cisplatin-induced, loss of viability (studied by MTT assay), production of reactive oxygen species (by DCFDA assay) and apoptosis (by flow-cytometry) in PC12 cells while it was increased in the two TNBC cells. Furthermore, we demonstrated that important genes associated with metastases, inflammation, chemoresistance and cell cycle progression are attenuated by SP-receptor antagonism in the TNBC cell line, Sum 185. These studies implicate that SP-receptor antagonism in combination with cisplatin may possibly serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC.

Growth Promotion and Increased ATP-Binding Cassette Transporters Expression by Liraglutide in Triple Negative Breast Cancer Cell Line MDA-MB-231

Drug Research ◽  
2021 ◽  
Author(s):  
Amir Shadboorestan ◽  
Parastoo Tarighi ◽  
Mahsa Koosha ◽  
Homa Faghihi ◽  
Mohammad Hossein Ghahremani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Abc Transporters ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Growth Promotion ◽  
Atp Binding ◽  
Mesenchymal Transition ◽  
Atp Binding Cassette

Background Glucagon-like petide-1 (GLP-1) agonists such as liraglutide are widely employed in type 2 diabetes due to their glucose reducing properties and small risk of hypoglycemia. Recently, it has been shown that GLP-1agonists can inhibit breast cancer cells growth. Nonetheless, concerns are remained about liraglutide tumor promoting effects as stated by population studies. Material and Methods We evaluated the effects liraglutide on proliferation of MDA-MB-231 cells by MTT assay and then ATP-binding cassette (ABC) transporters expressions assessed by Real time PCR. Statistical comparisons were made using one-way analysis of variance followed by a post hoc Dunnett test. Results Here, we report that liraglutide can stimulate the growth of highly invasive triple negative cell line MDA-MB-231; which can be attributed to AMPK-dependent epithelial-mesenchymal transition (EMT) happening in MDA-MB-231 context. Toxicity effects were only observed with concentrations far above the serum liraglutide concentration. ATP-binding cassette (ABC) transporters expressions were upregulated, indicating the possible drug resistance and increased EMT. Conclusion In conclusion, these results suggest that liraglutide should be used with caution in patients who are suffering or have the personal history of triple negative breast cancer. However, more detailed studies are required to deepen understanding of liraglutide consequences in triple negative breast cancer. ▶Graphical Abstract.

scholarly journals Mibefradil inhibits the proliferation of triple-negative breast cancer by targeting AURKA to regulate apoptosis signal pathway

2021 ◽  
Author(s):  
Xu Han ◽  
Xiujuan Qu ◽  
Beixing Liu ◽  
Yizhe Wang ◽  
Yang Cheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Molecular Docking ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Drug ◽  
Specific Gene ◽  
In Vivo Models

Abstract Background: Triple negative breast cancer (TNBC) is a tumor characterized by high recurrence and mortality, but without effective targeted therapy. It is urgent to explore new treatment strategy to improve the efficacy of TNBC therapy. Methods: Transcriptomic profiling datasets of TNBC were used for screening TNBC specific gene sets. Drug prediction was performed in Connectivity map (CMap) database. Molecular docking method was used for analyzing drug targets. In vitro and in vivo models of TNBC were constructed to examine the drug efficacy. Results: We screened out Mibefradil, a T-type Ca2+ channel blocker, might be a potential therapeutic drug for TNBC by transcriptomics and bioinformatics analysis, and verified that Mibefradil could inhibit the proliferation of TNBC cells by inducing apoptosis and cell cycle arrest. Furthermore, by network pharmacology and molecular docking analysis, AURKA was predicted as the most possible drug target of Mibefradil. Finally, it was proved that Mibefradil treatment could induce apoptosis by decreasing protein expression and phosphorylation level of AURKA in vitro and in vivo. Conclusions: Mibefradil played anti-cancer role in TNBC cells by targeting to AURKA to induce cell cycle and apoptosis. Our results repurposed Mibefradil as a potential targeted drug of TNBC and provided a fundamental research for a novel strategy TNBC treatment.

scholarly journals Meroterpenoids From Ganoderma lucidum Mushrooms and Their Biological Roles in Insulin Resistance and Triple-Negative Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiao-Jiao Zhang ◽  
Dai-Wei Wang ◽  
Dan Cai ◽  
Qing Lu ◽  
Yong-Xian Cheng
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Ganoderma Lucidum ◽  
Triple Negative ◽  
Raw Materials ◽  
Biological Evaluation ◽  
C2c12 Cells ◽  
Dependent Manner

Ganoderma fungi as popular raw materials of numerous functional foods have been extensively investigated. In this study, five pairs of meroterpenoid enantiomers beyond well-known triterpenoids and polysaccharides, dayaolingzhiols I−M (1–5), were characterized from Ganoderma lucidum. Their structures were identified using spectroscopic and computational methods. Structurally, compound 1 features a novel dioxabicyclo[2.2.2]octan-3-one motif in the side chain. Ethnoknowledge-derived biological evaluation found that (+)-5 could activate Akt and AMPK phosphorylation in insulin-stimulated C2C12 cells, and (+)-5 could activate glucose uptake dose dependently in C2C12 cells. Furthermore, we found that (+)-1 (+)-4, and (–)-4 could significantly inhibit cell migration of the MDA-MB-231 cell line, of which (+)-4 showed significant inhibitory effects against cell migration of the MDA-MB-231 cell line in a dose-dependent manner. These findings revealed the meroterpenoidal composition of G. lucidum and its roles in the prevention of chronic diseases such as diabetes mellitus and triple-negative breast cancer.

scholarly journals In vitro antineoplastic activity in triple-negative breast cancer cell line and in vivo

2014 ◽  
Vol 8 (Suppl 4) ◽  
pp. P22
Author(s):  
Klesia Madeira ◽  
Murilo Cerri ◽  
Renata Daltoé ◽  
Alice Herlinger ◽  
João Filho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Triple Negative ◽  
Cancer Cell Line
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