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

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.

Monoclonal Antibody Against Sortilin Induces Apoptosis in Human Breast Cancer Cells

Background: Sortilin has an important role in various malignances and can be used as a promising target to eradicate cancer cells. Methods: In this study, the expression of sortilin in 4T1 and MDA-MB231 cell lines was evaluated by flow cytometry and immunocytochemistry. Apoptosis assay was also applied to evaluate apoptosis induction in 4T1 and MDA-MB231 cell lines. Results: Based on cell surface flow cytometry results, anti-sortilin (2D8-E3) mAb could recognize sortilin molecules in 79.2% and 90.3% of 4T1 and MDA-MB231 cell-lines, respectively. The immunocytochemistry staining results confirmed sortilin surface expression. Apoptosis assay indicated that anti-sortilin mAb could induce apoptosis in 4T1 and MDA-MB231 cell lines. Conclusion: Our study revealed the important role of surface sortilin in breast carcinoma cell survival and its possible application as a therapeutic agent in cancer targeted therapies.

Colchicine: Isolation, LC–MS QTof Screening, and Anticancer Activity Study of Gloriosa superba Seeds

Colchicine was extracted from Gloriosa superba seeds using the Super Critical Fluid (CO2) Extraction (SCFE) technology. The seeds were purified upto 99.82% using column chromatography. Colchicine affinity was further investigated for anticancer activity in six human cancer cell lines, i.e., A549, MCF-7, MDA-MB231, PANC-1, HCT116, and SiHa. Purified colchicine showed the least cell cytotoxicity and antiproliferation and caused no G2/M arrest at clinically acceptable concentrations. Mitotic arrest was observed in only A549 and MDA-MB231 cell lines at 60nM concentration. Our finding indicated the possible use of colchicine at a clinically acceptable dose and provided insight into the science behind microtubule destabilization. However, more studies need to be conducted beforethese findings could be established.

Thapsigargin, inhibitor of sarco-endoplasmic Ca2+-ATPase, effectively suppresses the expression of S100A4 in human breast cancer cell line

Thapsigargin, the SERCA ATPase inhibitor, effectively suppresses the expression of metastasis marker S100A4 in breast cancer cells MDA-MB231. It has been demonstrated that transcription of the S100A4 gene is controlled by Ca2+-signaling pathways. It has been shown that synthesis of S100A4 mRNA and protein in the MDA-MB231 cell line is effectively inhibited by thapsigargin at a concentration of 0.4-4 µM, while preserving cell survival. We assume that a change in gene transcription in response to the disruption of Ca2+ homeostasis plays a direct role in the remodeling of Ca2+-signaling pathways.

Synthesis, Anticancer Activity, and Apoptosis Induction of Novel 3,6-Diazaphenothiazines

New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell lines, depending on the nature of the substituents. The most active 3,6-diazaphenothiazine, 4, was the derivative with the N,N-diethylamino-2-butynyl substituent against glioblastoma SNB-19, and was ten times more potent than cisplatin. For this compound, the expression of H3, TP53, CDKN1A, BCL-2, and BAX genes was detected by the RT-qPCR method. The gene expression ratio BAX/BCL-2 indicated the induction of mitochondrial apoptosis in cancer cell lines. The transformation of the propynyl substituent into amino-2-butynyl can be a method applicable to the search for more anticancer-active azaphenothiazines.

Synthesis of Paclitaxel Loaded on Nanoparticles of Archaeosomes and Investigation of Its Anti-cancer Properties

Objective: In this study, the effect of archaeosomal paclitaxel drug on breast cancer MDA-MB231 cell lines was evaluated. Material and method: The experiments were conducted to assess the cytotoxicity of paclitaxel in free form and compare it with archaeosomal form of the drug in vitro. To check the size of archaeosomes, Zetasizer device (DLS) was used. The average size of archaeosom nanoparticles containing paclitaxel drugs 430 nm and surface charge -15 and the average size of control archaeosom nanoparticles without drug 460 nm and surface charge -14 were reported. The effect of archaeosomal drug containing paclitaxel and free drug were examined by MTT test.Results: In both formulations, zeta potential was negative. Nano-archaeosom containing paclitaxel drug had higher physical stability compared with control nano-Archaeosom. Tests showed the killing effect of nano-archaeosome containing paclitaxel formulation tumor cells was more than free formulation. In the other word, nano-archaeosome containing paclitaxel is more effective than free paclitaxel.Conclusion: The experiments showed that the killing effect of tumor cells of nano-archaeosomes formulations containing paclitaxel was more than free formulation. That is, nano-archaeosomes containing paclitaxel was more effective than free form paclitaxel.

The Influence of Different Oregano Species on the Antioxidant Activity Determined Using HPLC Postcolumn DPPH Method and Anticancer Activity of Carvacrol and Rosmarinic Acid

The aim of this study was to evaluate concentration-dependent antioxidant and anticancer activities of CA and RA in ethanol extracts of three different Oregano species (Origanum onites L., Origanum vulgare L., and Origanum vulgare ssp. hirtum). The study revealed the highest RA antioxidant activity in O. vulgare ssp. hirtum (9550±95 mmol/g) and the lowest in O. vulgare L. (2605±52 mmol/g) (p<0.05). The highest CA amount was present in O. onites L., which was 1.8 and 4.7 times higher (p<0.05) than in O. vulgare ssp. hirtum and O. vulgare L., respectively. The anticancer activity was evaluated on human glioblastoma (U87) and triple-negative breast cancer (MDA-MB231) cell lines in vitro. RA anticancer activity was negligible. CA and the extracts were about 1.5–2 times more active against MDA-MB231 cell line (p<0.05) compared to U87 cell line. The anticancer activities of three tested extracts were similar against U87 cell line (p>0.05) but they had different activities against MDA-MB231 cell line.