Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

Abdalla, Ashraf N.; Qattan, Amal; Malki, Waleed H.; Shahid, Imran; Hossain, Mohammad Akbar; Ahmed, Muhammad

doi:10.3390/molecules25204606

Cited by 23 publications

(9 citation statements)

References 53 publications

(75 reference statements)

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“…The PamChip ® peptide microarray-based kinase activity profiling assays were done as previously described [ 32 ]. The immobilized peptides in the PamChip ® micro-arrays can be phosphorylated by the kinases present in the investigated sample(s) in the presence of ATP.…”

Section: Methodsmentioning

confidence: 99%

“…The immunofluorescence staining was used to test the effect of the compounds on EGFR and caspase 8 in HT29 cells, p27 and p21 in HT29-5FU cells according to a previous report [ 32 ]. Cells (2 × 10 5 /chamber) were incubated (72h) with vehicle, 5FU (0.25 µM), HAA 2020 (3 µM), or their combination.…”

Section: Methodsmentioning

confidence: 99%

“…The STK (serine/threonine kinase) and the PTK (phosphorylation by tyrosine kinase of immobilized peptides) are the two assays that can be utilized in the PamChip ® platform. In the STK, a combination of FITC-labeled secondary antibody and anti-phospho-serine/threonine antibodies can be used for detection of peptide phosphorylation, while the FITC-labeled and anti-phospho-tyrosine antibodies are used in the PTK application [ 29 , 30 , 31 , 32 ]. Thus, the determination of the differentially overexpressed and CRC-associated kinases in a specific population could facilitate better selection of CRC drugs or drug combinations that can reverse resistance.…”

Section: Introductionmentioning

confidence: 99%

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Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer

et al. 2021

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Colorectal cancer (CRC) remains one of the main causes of death worldwide and in Saudi Arabia. The toxicity and the development of resistance against 5 fluorouracil 5FU pose increasing therapeutic difficulties, which necessitates the development of personalized drugs and drug combinations. Objectives: First, to determine the most important kinases and kinase pathways, and the amount of ABC transporters and KRAS in samples taken from Saudi CRC patients. Second, to investigate the chemosensitizing effect of LY294002 and HAA2020 and their combinations with 5FU on HT29, HT29-5FU, HCT116, and HCT116-5FU CRC cells, their effect on the three ABC transporters, cell cycle, and apoptosis, in light of the important kinase pathways resulting from the first part of this study. Methods: The PamChip® peptide micro-array profiling was used to determine the level of kinase and targets in the Saudi CRC samples. Next, RT-PCR, MTT cytotoxicity, Western blotting, perturbation of cell cycle, annexin V, and immunofluorescence assays were used to investigate the effect on CRC, MRC5, and HUVEC cells. Results: The kinase activity profiling highlighted the importance of the PI3K/AKT, MAPK, and the growth factors pathways in the Saudi CRC samples. PIK3CA was the most overexpressed, and it was associated with increased level of mutated KRAS and the three ABC transporters, especially ABCC1 in the Saudi samples. Next, combining HAA2020 with 5FU exhibited the best synergistic and resistance-reversal effect in the four CRC cells, and the highest selectivity indices compared to MRC5 and HUVEC normal cells. Additionally, HAA2020 with 5FU exerted significant inhibition of ABCC1 in the four CRC cells, and inhibition of PIK3CA/AKT/MAPK7/ERK in HT29 and HT29-5FU cells. The combination also inhibited EGFR, increased the preG1/S cell cycle phases, apoptosis, and caspase 8 in HT29 cells, while it increased the G1 phase, p21/p27, and apoptosis in HT29-5FU cells. Conclusion: We have combined the PamChip kinase profiling of Saudi CRC samples with in vitro drug combination studies in four CRC cells, highlighting the importance of targeting PIK3CA and ABCC1 for Saudi CRC patients, especially given that the overexpression of PIK3CA mutations was previously linked with the lack of activity for the anti-EGFRs as first line treatment for CRC patients. The combination of HAA2020 and 5FU has selectively sensitized the four CRC cells to 5FU and could be further studied.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer

et al. 2021

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“…To investigate the ability of compound 16g to induce apoptosis, MCF7 cells were treated with three different concentrations (0.01, 0.05, and 0.10 μM) of the test compound following the previous report [ 37 ]. The results showed that compound 16g induced a dose-dependent increase in the apoptotic events in MCF7 cells compared to the control group (from 7.9–17.8%), Figure 13 .…”

Section: Resultsmentioning

confidence: 99%

“…MCF7 cells were treated by compound 16g at 0.00, 0.01, 0.05 and 0.10 μM final concentrations for 72 h. Briefly, the superanent of the cells was collected in ice-cold tubes, trypsinized and incubated (37 °C). The procedures were completed following the previous report [ 37 ]. The samples were analyzed using flow cytometry (BC, FC500, Brea, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases

et al. 2021

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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a–h were discussed. The antiproliferative activity of 16a–h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01–40.50 μM) and one normal MRC5 (IC50 = 1.27–24.06 μM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 μM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.

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