Proton pump inhibitors enhance chemosensitivity, promote apoptosis, and suppress migration of breast cancer cells

Breast cancer is the most common cancer and is the leading cause of cancer deaths among women worldwide. Despite the availability of numerous therapeutics for breast cancer management, cytotoxicity and emergence of drug resistance are major challenges that limit their benefits. The acidic microenvironment surrounding tumor cells is a common feature inducing cancer cell invasiveness and chemoresistance. Proton pump inhibitors (PPIs) are one of the most commonly prescribed drugs for the treatment of acid-related conditions. PPIs have been reported to exhibit antitumorigenic effects in many cancer types. In this study, the anti-proliferative and anti-migratory effects of PPIs in three breast cancer cell lines; MCF-7, T47D, and MDA-MB-231 cells, have been investigated. In addition, the combined effects of PPIs with anticancer drugs, as well as the mechanism of PPI-mediated anti-proliferative activity were evaluated. The anti-proliferative and combined effects of PPIs were evaluated by MTT assay. Cell migration was assessed using the wound-healing assay. The mechanism of cell death was assessed using annexin V-FITC/ propidium iodide staining flow cytometry method. Our results indicated that PPIs treatment significantly inhibited the growth of breast cancer cells in a dose-dependent manner. The antiproliferative activity of PPIs was significantly induced by apoptosis in all tested cell lines. The combined treatment of PPIs with doxorubicin resulted in a synergistic effect in all cell lines, whereas thehile combined treatment with raloxifene exhibited synergistic effect in T47D cells only and additive effects in MDA-MB-231 and MCF-7 cells. In addition, PPIs treatment significantly reduced cell migration in MDA-MB-231 cells. In conclusion, the addition of PPIs to the treatment regimen of breast cancer appears to be a promising strategy to potentiate the efficacy of chemotherapy and may suppress cancer metastasis

An in vitro based investigation into the cytotoxic effects of D-amino acids

In the present study, cytotoxic effects of D-Ala, D-Pro and D-Lys are demonstrated. In an effort to study possible mechanisms of the observed cytotoxicity, catalase activity, H2O2 generation, and apoptotic activity were measured in HeLa and MCF-7 cell lines. Although D-Lys is a poor substrate for DAO and therefore low H2O2 has been detected, it was shown to provoke severe impairment of cellular integrity and survival. Interestingly, a very good substrate for DAO, such as D-Pro, did not substantially reduce cell viability. On the other hand, a moderate substrate for DAO, represented by D-Ala, was shown to moderately trigger toxicity in the tested cell lines. Although a correlation between the in vitro cytotoxicity of D-amino acids and the amount of H2O2 produced was absent, there was a good agreement between the ability of D-amino acids to trigger apoptosis and to provoke toxicity. Our results indicate that the toxicity of D-amino acids does not appear to be solely mediated by H2O2. Therefore, we hypothesize that other possible contributing apoptosis-mediated pathways might cause the observed toxicity

Sitagliptin: a potential drug for the treatment of COVID-19?

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality

Glucose deprivation enhances the antiproliferative effects of oral hypoglycemic biguanides in different molecular subtypes of breast cancer: An in vitro study

Extensive in vitro studies have been conducted to evaluate the anticancer activity of oral hypoglycemic agents. Many of these studies experienced detrimental limitations, since they were conducted on cancer cells commonly grown in culture media consisting of extremely high concentrations of growth factors and glucose. The present study was aimed at exploring the antiproliferative effects of the commonly studied metformin and the less frequently reported phenformin oral hypoglycemic agents on different molecular subtypes of breast cancer under rich glucose and glucose deprived conditions. Our results indicate that under glucose deprived conditions, which better reflect the factual glucose-starved solid tumors in vivo, biguanides exert more antiproliferative activities against the three molecular subtypes of breast cancer cell lines examined in this study. In addition, the observed antiproliferative activities of biguanides appear to be mediated by apoptosis induction in breast cancer cells. This induction is significantly augmented under glucose deprived conditions

Computer-aided discovery of antimicrobial agents as potential enoyl acyl carrier protein reductase inhibitors

Purpose: To perform a virtual screening for a set of drug-like ligand library against the Staphylococcus aureus enoyl acyl carrier protein reductase, saFabI.Methods: The virtual screening was conducted based on a previously validated pharmacophoreconstrained docking. Consequently, the top list obtained was filtered using visual inspection where forty compounds were selected for experimental testing using disk-diffusion test and broth dilution method. The hits obtained were checked for their toxicity against human fibroblasts cell lines.Results: Three compounds were active against Staphylococcus aureus and other tested gram-positive bacteria. However, no significant inhibitory activity (p < 0.05) was detected against Escherichia coli or Candida albicans. The minimum inhibitory concentration (MIC) values for the most active compounds were identified using the broth dilution method; all of them exhibited inhibitory activity within micromolar range.The docking results showed that the hits obtained exhibited a small size with a nice binding mode to saFabI enzyme, forming the important interactions with the key residues. Furthermore, the best three hits demonstrated good safety profile as they did not show any significant toxicity against human fibroblast cell line.Conclusion: Overall, the newly discovered hits can act as a good starting point in the future for the development of safe and potent antibacterial agents.Keywords: Enoyl acyl carrier protein reductase, saFabI, Antibacterial agents, Docking, Constraint, Virtual screening Tropical Journal of Pharmaceutica

Phenolic compounds and bioactivity of Cytisus villosus Pourr.

The present study focuses on the chemical composition, antioxidant, antimicrobial, and anti proliferative activities of the ethyl acetate and aqueous extracts obtained from the aerial parts of Cytisus villosus Pourr. HPLC-DAD-ESI/MSn was used to identify the phenolic compounds, being (epi)gallocatechin dimer the major compound (111 ± 5 µg/g·dw) in the aqueous extract, while myricetin-O-rhamnoside(226±9 µg/g·dw) was the main molecule in the ethyl acetate extract. Both extracts exhibited good scavenging activities against DPPH radical(EC50 µg/mLof59±2and31±2 for aqueous and ethyl acetate extracts,respectively). However,the ethyl acetate extract demonstrated more potent quenching activities than the aqueous extract.The antimicrobial activities were assessed on selected Gram-positive (Staphylococcus epidermidis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria, as well as on pathogenic fungus Candida glabrata. The extracts possessed selective and potent antimicrobial activities against the Gram-positive bacterium (IC50 of 186±9 µg/mL and 92±3 µg/mL for aqueous and ethyl acetate extracts, respectively).Finally, C. villosus extracts were evaluated for their antiproliferative potential on three human cancer cell lines representing breast and colon cancers. Although both extracts demonstrated sufficient growth inhibition of the threed ifferent cell lines,the ethyl acetate extract exhibited higher activity(LD50 values of1.57±0.06mg/mL,2.2±0.1mg/mL,and3.2±0.2mg/mLforT47D,MCF-7,andHCT-116cell lines). Both the extracts obtained from the aerial parts of C.villosus revealed very promising results and could be applied as functional agents in the food,pharmaceutical,and cosmeceutical industries.The authors are grateful to the University of Jordan-Deanship of Academic Research (Jordan), the Foundation for Science and Technology (FCT, Portugal) and FEDER under Programme PT2020 for financial support to CIMO (UID/AGR/00690/2013) and L. Barros contract. The authors are also grateful to FEDER-Interreg España-Portugal programme for financial support through the project 0377_Iberphenol_6_E. APC was sponsored by MDPI.info:eu-repo/semantics/publishedVersio

Docking, synthesis, and anticancer assessment of novel quinoline-amidrazone hybrids

A group of new amidrazone compounds that include a quinoline component was produced through the reaction of hydrazonyl chloride, derived from 6-aminoquinoline, with appropriate secondary cyclic amines. The new compounds were confirmed through 1H-NMR, 13C-NMR, FTIR, and HRMS, and further verified by single-crystal X-ray diffraction. The antitumor potential of the synthesized compounds was tested against lung cancer (A549) and breast cancer (MCF-7) cell lines. Among the compounds, the ethyl carboxylate and o-hydroxy phenyl piperazine derivatives (10d and 10g) exhibited the strongest activity against both cell lines, with IC50 values of 43.1 and 59.1 μM for the lung and breast cancer cell lines, respectively. Moreover, the most potent compounds were subsequently docked into the c-Abl kinase binding site (PDB code: 1IEP) as a possible anticancer mechanism. In-silico ADMET study shows acceptable pharmacokinetic properties, and the toxicity profile for the most potent compounds is non-carcinogenic

Sitagliptin: a potential drug for the treatment of COVID-19?

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality