prodigiosin and Triple-Negative-Breast-Neoplasms

Triple-Negative Breast Cancer (TNBC) is found to be one of the life-threatening cancer. Poly (ADP-Ribose) Polymerase-1 (PARP-1) is overexpressed by those tumour cells, which become resistant to chemotherapies. Inhibition of PARP-1 has a considerable effect on treating TNBC. Prodigiosin is a valuable pharmaceutical compound that exhibits anticancer properties. The present study aims to virtually evaluate prodigiosin as a potent PARP-1 inhibitor using Molecular docking and Molecular Dynamics (MD) simulation studies. The PASS (Prediction of Activity Spectra for Substances) prediction tool evaluated the biological properties of prodigiosin. Then the drug-likeness and pharmacokinetic properties of prodigiosin were determined using Swiss-ADME software. It was suggested that prodigiosin obeyed Lipinski's rule of five and thus could act as a drug with good pharmacokinetic properties. Moreover, molecular docking was done with AutoDock 4.2 to identify the critical amino acids of the protein-ligand complex. It was indicated that prodigiosin has a docking score of -8.08 kcal/mol, which showed its effective interaction with crucial amino acid, His201A of PARP-1 protein. Further, MD simulation was performed using Gromacs software to validate the stability of the prodigiosin-PARP-1 complex. Prodigiosin was found to have good structural stability and affinity at the active site of PARP-1 protein. Additionally, PCA and MM-PBSA were calculated for the prodigiosin-PARP-1 complex, which revealed that prodigiosin has an excellent binding affinity towards PARP-1 protein. Prodigiosin can possibly be used as oral drug due to its PARP-1 inhibition through high binding affinity, structural stability, and receptor flexibility towards crucial amino acid residue His201A of PARP-1 protein. In-addition, in-vitro cytotoxicity, and apoptosis analysis of prodigiosin-treated TNBC cell line-MDA-MB-231 revealed that prodigiosin exhibited significant anticancer activity in 101.1 µg/mL concentration, when compared to commercially available synthetic drug cisplatin. Thus, prodigiosin could act as a potential candidate for treatment of TNBC than the commercially available synthetic drugs.

Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Molecular Docking Simulation; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Prodigiosin; Triple Negative Breast Neoplasms

The paper presents the results of the experimental and analytical study of targeted drug-loaded polymer-based microspheres made from blend polymer of polylactic-co-glycolic acid and polycaprolactone (PLGA-PCL) for targeted and localized cancer drug delivery. In vitro sustained release with detailed thermodynamically driven drug release kinetics, over a period of three months using encapsulated targeted drugs (prodigiosin-EphA2 or paclitaxel-EphA2) and control drugs [Prodigiosin (PGS), and paclitaxel (PTX)] were studied. Results from in vitro study showed a sustained and localized drug release that is well-characterized by non-Fickian Korsmeyer-Peppas kinetics model over the range of temperatures of 37 °C (body temperature), 41 °C, and 44 °C (hyperthermic temperatures). The in vitro alamar blue, and flow cytometry assays in the presence of the different drug-loaded polymer formulations resulted to cell death and cytotoxicity that was evidence through cell inhibition and late apoptosis on triple negative breast cancer (TNBC) cells (MDA-MB 231). In vivo studies carried out on groups of 4-week-old athymic nude mice that were induced with subcutaneous TNBC, showed that the localized release of the EphA2-conjugated drugs was effective in complete elimination of residual tumor after local surgical resection. Finally, ex vivo histopathological analysis carried out on the euthanized mice revealed no cytotoxicity and absence of breast cancer metastases in the liver, kidney, and lungs 12 weeks after treatment. The implications of the results are then discussed for the development of encapsulated EphA2-conjugated drugs formulation in the specific targeting, localized, and sustain drug release for the elimination of local recurred TNBC tumors after surgical resection.

Topics: Animals; Cell Line, Tumor; Humans; Mice; Mice, Nude; Microspheres; Nanoparticles; Paclitaxel; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Prodigiosin; Triple Negative Breast Neoplasms

Prodigiosin, a secondary metabolite red pigment produced by Serratia marcescens, has an interesting apoptotic efficacy against cancer cell lines with low or no toxicity on normal cells. HSP90α is known as a crucial and multimodal target in the treatment of TNBC. Our research attempts to assess the therapeutic potential of prodigiosin/PU-H71 combination on MDA-MB-231 cell line. The transcription and protein expression levels of different signalling pathways were assessed. Treatment of TNBC cells with both drugs resulted in a decrease of the number of adherent cells with apoptotic effects. Prodigiosin/PU-H71 combination increased the levels of caspases 3,8 and 9 and decreased the levels of mTOR expression. Additionally, there was a remarkable decrease of HSP90α transcription and expression levels upon treatment with combined therapy. Also, EGFR and VEGF expression levels decreased. This is the first study to show that prodigiosin/PU-H71 combination had potent cytotoxicity on MDA-MB-231 cells; proving to play a paramount role in interfering with key signalling pathways in TNBC. Interestingly, prodigiosin might be a potential anticancer agent to increase the sensitivity of TNBC cells to apoptosis. This study provides a new basis for upcoming studies to overcome drug resistance in TNBC cells.

Topics: Antineoplastic Agents; Apoptosis; Benzodioxoles; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; ErbB Receptors; Female; HSP90 Heat-Shock Proteins; Humans; Prodigiosin; Purines; Signal Transduction; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A

Hybrid composite nanofibers, with the potential to enhance cell adhesion while improving sustained drug release profiles, were fabricated by the blend electrospinning of poly(d,l-lactic-co-glycolic acid) (PLGA), gelatin, pluronic F127 and prodigiosin (PG). Scanning Electron Microscopy (SEM) images of the nanofibers revealed diameters of 1.031 ± 0.851 μm and 1.349 ± 1.264 μm, corresponding to PLGA/Ge-PG and PLGA/Ge-F127/Ge, respectively. The Young's moduli were also determined to be 1.446 ± 0.496 kPa and 1.290 ± 0.617 kPa, while the ultimate tensile strengths were 0.440 ± 0.117 kPa and 0.185 ± 0.480 kPa for PLGA/Ge-PG and PLGA/Ge-F127/Ge, respectively. In-vitro drug release profiles showed initial (burst) release for a period of 1 h to be 26.000 ± 0.004% and 16.000 ± 0.015% for PLGA/Ge and PLGA/Ge-F127 nanofibers, respectively. This was followed by 12 h of sustained release, and subsequent slow sustained release of PG from the composite nanofibers. The cumulative release of PG (for three days) was determined to be 82.0 ± 0.1% for PLGA/Ge and 49.7 ± 0.1% for PLGA/Ge-F127 nanofibers. The release exponents (n) show that both nanofibers exhibit diffusion-controlled release by non-Fickian (zeroth order) and quasi-Fickian diffusion in the initial and sustained release regimes, respectively. The suitability of the composite nanofibers for supporting cell proliferation and viability, as well as improving sustained release of the drug were explored. The in-vitro effects of cancer drug (PG) release were also studied on breast cancer cell lines (MCF-7 and MDA-MB-231 cells). The implications of the results are discussed for the potential applications of drug-nanofiber scaffolds as capsules for localized delivery of chemotherapeutic drugs for the treatment of triple negative breast cancer.

Topics: Humans; Nanofibers; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prodigiosin; Triple Negative Breast Neoplasms

This paper presents the anomalous release kinetics of a cancer drug (prodigiosin) frompoly-n-isopropyl-acrylamide (P(NIPA))-based gels. The release exponents, n, which correspond to the drug release mechanisms, were found to be between 0.41 and 1.40. This is within a range that include Fickian case I (n = 0.45) and non-Fickian diffusion (case II) (n > 0.45) for cylindrical drug-loaded structures. The results, however, suggest that the release exponents, n, correspond mostly to anomalous case II and super case II transport mechanics with sigmoidal characteristics. The drug release kinetics of the P(NIPA)-based hydrogels are well described by bi-dose functions. The observed drug release behavour is related to the porosity of the hydrogels, which can be controlled by cross-linking and copolymerization with acrylamide, which also improves the hydrophilicity of the gels. The paper also presents the effects of cancer drug release on cell survival (%), as well as the cell metabolic activities of treated cells and non-treated cells. The implications of the results are discussed for the development of implantable thermosensitive gels for the controlled release of drugs for localized cancer treatment.

Topics: Acrylic Resins; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Carriers; Humans; Hydrogels; Hydrophobic and Hydrophilic Interactions; Kinetics; Porosity; Prodigiosin; Triple Negative Breast Neoplasms

This paper explores the adhesion of biosynthesized gold nanoparticles (AuNPs) and gold (Au) nanoparticle/prodigiosin (PG) drug nanoparticles to breast cancer cells (MDA-MB-231 cells). The AuNPs were synthesized in a record time (less than 30 s) from Nauclea latifolia leaf extracts, while the PG was produced via bacterial synthesis with Serratia marcescens sp. The size distributions and shapes of the resulting AuNPs were characterized using transmission electron microscopy (TEM), while the resulting hydrodynamic diameters and polydispersity indices were studied using dynamic light scattering (DLS). Atomic Force Microscopy (AFM) was used to study the adhesion between the synthesized gold nanoparticles (AuNPs)/LHRH-conjugated AuNPs and triple negative breast cancer cells (MDA-MB-231 cells), as well as the adhesion between LHRH-conjugated AuNP/PG drug and MDA-MB-231 breast cancer cells. The adhesion forces between LHRH-conjugated AuNPs and breast cancer cells are shown to be five times greater than those between AuNPs and normal breast cells. The increase in adhesion is shown to be due to the over-expression of LHRH receptors on the surfaces of MDA-MB-231 breast cancer cells, which was revealed by confocal immuno-fluorescence microscopy. The implications of the results are then discussed for the selective and specific targeting and treatment of triple negative breast cancer.

Topics: Adsorption; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Combined Modality Therapy; Drug Delivery Systems; Female; Gold; Humans; Hyperthermia, Induced; Metal Nanoparticles; Microscopy, Atomic Force; Prodigiosin; Triple Negative Breast Neoplasms