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Backgrounds: Targeting breast cancer stem cells with the CD44+/CD24-phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and therapeutic resistance ability. Quercetin is a popular flavonoid with lower adverse effects and has anti-tumor properties. Therefore, we assessed the anticancer activity of Quercetin and Doxorubicin alone and in combination in the T47D cells of human breast cancer and their isolated Cancer stem cells (CSCs). Materials and Methods: The human breast cancer cell line T47D was used for this experiment. T47D CSCs were isolated by magnetic bead sorting using the MACS system. The anticancer activity of Quercetin and Doxorubicin alone and in combination were evaluated using MTT cytotoxicity assay and cell cycle distribution and apoptosis induction by flow cytometry analysis. Results: We have shown that almost 1% of T47D cell populations are made up of CD44+/CD24-cells, which considered as cancer stem cells. Quercetin and Doxorubicin alone or in combination inhibited cell proliferation and induced apoptosis in breast cancer T47D cells and in lower extent in CD44+/CD24-cells. Quercetin significantly strengthened Doxorubicin's cytotoxicity and apoptosis induction in both cell populations. Quercetin and Doxorubicin and their combination induced G2/M arrest in the T47D cells and to a lesser extent in isolated CSCs. A value of p < 0.05 was considered as indicating a statistically significant difference. Conclusion: These outcomes suggested that CSCs are a minor population of cancer cells, which play a significant role in drug resistance by being quiescent, slow cycling and resistance to apoptosis. Furthermore, our data showed that adding Quercetin to Doxorubicin is an effective approach for the treatment of both CSCs and bulk tumor cells.

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Heparin and heparan sulfate are important glycosaminoglycans that can regulate the activities of many vital proteins, especially the fibroblast growth factor (FGF) family.Because FGF7 (KGF) has an important role in tissue repair and maintaining the integrity of the mucosal barrier, recombinant human keratinocyte growth factor (rhKGF, palifermin) has been approved for the treatment of wound healing and oral cavity.Due to heparin plays an important role in the KGF signaling pathway, a more detailed study of the drug-drug interactions (DDIs) between rhKGF and heparin at the atomic level and investigating their synergistic effect on each other in terms of biology, especially in silico, is necessary for a better understanding of DDIs. In this study, DDIs between rhKGF and low-molecular weight heparin types (LMWH) were investigated.In this regard, scrutiny of the influence of the synergistic heparin types on the structure and biostability of rhKGF is accomplished using computational methods such as molecular docking and molecular dynamic simulations (MDs). Subsequently, the motion behavior of rhKGF in interaction with LMWHs was evaluated based on eigenvectors by using principal component analysis (PCA). Also, the binding free energies of rhKGF-LMWH complexes were calculated by the molecular mechanics/Poisson-Boltzmann surface area (MM-BPSA) method. The result showed that rhKGFidraparinux (À6.9 kcal/mol) and rhKGF-heparin (À6.0 kcal/mol) complexes had significant binding affinity as well as they had a more stable binding to rhKGF than to other LMWH during 100 ns simulation. However, in order to confirm the curative effect of these drugs, clinical trials must be done.Abbreviations: 2-D structure, two-dimensional structure; AUC, area under the curve; CL, average total body clearance; FGF, fibroblast growth factor; HS, heparin sulfate; KGF, keratinocyte growth factor; LINCS, linear constraint solver; LMWH, low-molecular weight heparin; MD, molecular dynamics; MM-PBSA, molecular mechanics-PoissonBoltzmann surface area; MW, molecular weight; NPT, constant number of particles, pressure, and temperature; NVT, constant number of particles, volume, and temperature; OM, oral mucositis; PCA, principal component analysis; PDB, Protein Data Bank; R g , radius of gyration; rhKGF, recombinant human keratinocyte growth factor; RMSD, root mean square deviation; RMSF, root mean square fluctuations; UH, unfractionated heparin; ULMWH, ultra-low molecular weight heparin; Vss, volume of distribution at steady state; ΔE ele , electrostatic contribution; ΔE MM , energy of the molecular mechanics; ΔE vdw , Van der Waals contributions; ΔGnonpol, nonpolar contribution; ΔGpol, polar solvation contribution.