scholarly journals Humanized anti-DEspR IgG4S228P antibody increases overall survival in a pancreatic cancer stem cell-xenograft peritoneal carcinomatosis ratnu/nu model

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Christopher M. Gromisch ◽  
Glaiza L. A. Tan ◽  
Khristine Amber Pasion ◽  
Ann-Marie Moran ◽  
Matthew S. Gromisch ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peritoneal Carcinomatosis ◽  
Protein Function ◽  
Apoptotic Cell ◽  
Metastatic Cancer ◽  
Apoptosis Resistance ◽  
Anoikis Resistance ◽  
Nuclear Shuttling ◽  
Cell Changes

Abstract Background Pancreatic peritoneal carcinomatosis (PPC), with the worst median overall-survival (mOS), epitomizes the incurability of metastatic cancer. Cancer stem cells (CSCs) underpin this incurability. However, inhibitors of CSC-stemness fail to increase mOS in cancer patients despite preclinical tumor-reduction. This shortfall reinforces that preclinical efficacy should be defined by increased mOS in the presence of cancer comorbidities, CSC-heterogeneity and plasticity. The primary objectives of this study are: to test the dual endothelin-1/signal peptide receptor, DEspR, as a nodal therapeutic target in PPC, given DEspR induction in anoikis-resistant pancreatic CSCs, and to validate humanized anti-DEspR antibody, hu-6g8, as a potential therapeutic for PPC. Methods We used heterogeneous pools of CSCs selected for anoikis resistance from reprogrammed Panc1 and MiaPaCa2 tumor cells (TCs), and adherent TCs reprogrammed from CSCs (cscTCs). We used multiple anti-DEspR blocking antibodies (mAbs) with different epitopes, and a humanized anti-DEspR recombinant mAb cross-reactive in rodents and humans, to test DEspR inhibition effects. We measured DEspR-inhibition efficacy on multiple prometastatic CSC-functions in vitro, and on tumorigenesis and overall survival in a CSC-derived xenograft (CDX) nude rat model of PPC with comorbidities. Results Here we show that DEspR, a stress-survival receptor, is present on subsets of PDAC Panc1-TCs, TC-derived CSCs, and CSC-differentiated TCs (cscTCs), and that DESpR-inhibition decreases apoptosis-resistance and pro-metastatic mesenchymal functions of CSCs and cscTCs in vitro. We resolve the DNA-sequence/protein-function discordance by confirming ADAR1-RNA editing-dependent DEspR-protein expression in Panc1 and MiaPaCa2 TCs. To advance DEspR-inhibition as a nodal therapeutic approach for PPC, we developed and show improved functionality of a recombinant, humanized anti-DEspR IgG4S228P antibody, hu-6g8, over murine precursor anti-DEspR mabs. Hu-6g8 internalizes and translocates to the nucleus colocalized with cyto-nuclear shuttling galectins-1/3, and induces apoptotic cell changes. DEspR-inhibition blocks transperitoneal dissemination and progression to peritoneal carcinomatosis of heterogeneous DEspR±/CD133 ± Panc1-derived CSCs in xenografted nude rats, improving mOS without chemotherapy-like adverse effects. Lastly, we show DEspR expression in Stage II-IV primary and invasive TCs in the stroma in PDAC-patient tumor arrays. Conclusion Collectively, the data support humanized anti-DEspR hu-6g8 as a potential targeted antibody-therapeutic with promising efficacy, safety and prevalence profiles for PPC patients.

scholarly journals PP2A inhibitor PME-1 suppresses anoikis, and is associated with therapy relapse of PTEN-deficient prostate cancers

2019 ◽  
Author(s):  
Christian Rupp ◽  
Anna Aakula ◽  
Aleksi Isomursu ◽  
Andrew Erickson ◽  
Otto Kauko ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Progression ◽  
Tumor Model ◽  
Nuclear Lamina ◽  
Metastatic Progression ◽  
Apoptosis Resistance ◽  
Anoikis Resistance ◽  
In Ovo

AbstractIdentification of novel mechanisms of apoptosis resistance of prostate cancer (PCa) cells has translational importance. Here, we discover that inhibition of tumor suppressor phosphatase PP2A by PME-1 inhibits anoikis (apoptosis in anchorage-independent conditions) in PTEN-deficient PCa cells. PME-1 physically associated with the nuclear lamina and regulated its deformability in PCa cells. In addition, PME-1 deficient cells, with highly deformable nuclear lamina, were particularly vulnerable to anoikis following cell detachment. As a molecular explanation for increased nuclear lamina deformability, PME-1 depletion induced dephosphorylation of nuclear lamina constituents, Lamin-A/C, Lamin-B1, Lamin-B2, LAP2A, LAP2B, and NUP98. PME-1 inhibition increased apoptosis also in anin ovotumor model, and attenuated cell survival in zebrafish circulation. Clinically, PCa patients with inhibition of both PP2A and PTEN tumor suppressor phosphatases (PME-1high/PTENloss), have less than 50% 5-year secondary-therapy free patient survival, which is significantly shorter than survival of patients with only PTEN-deficient tumors.In summary, we discover that PME-1 overexpression supports anoikis resistance in PTEN-deficient PCa cells. Further, increased nuclear lamina deformability was identified as plausible target mechanism sensitizing PME-1-depleted cells to anoikis. Clinically, the results identify PME-1 as a novel candidate biomarker for particularly aggressive PTEN-deficient PCa.Clinical relevanceWhile organ-confined PCa is mostly manageable, the local and distant metastatic progression of PCa remains a clinical challenge. Resistance to anoikis is critical for PCa progression towards aggressive CRPC. Our data show that PME-1 expression in human PCa cells protects the cells from apoptosis induction in anchorage-independent conditions bothin vitroandin vivo. Clinically, our results identify PME-1 as a novel putative biomarker for extremely poor prognosis in PTEN-deficient PCa. Taken together, our results demonstrate novel post-translational regulation of key cancer progression mechanisms, with clear translational implications.

scholarly journals Different Frequency of Cyclic Tensile Strain Relates to Anabolic/Catabolic Conditions Consistent with Immunohistochemical Staining Intensity in Tenocytes

2020 ◽  
Vol 21 (3) ◽  
pp. 1082 ◽  
Author(s):  
Yusuke Kubo ◽  
Bernd Hoffmann ◽  
Katja Goltz ◽  
Uwe Schnakenberg ◽  
Holger Jahr ◽  
...  
Keyword(s):  
Protein Level ◽  
Immunohistochemical Staining ◽  
Apoptotic Cell ◽  
Staining Intensity ◽  
Cell Physiology ◽  
The Matrix ◽  
Cell Changes ◽  
Endothelial Growth Factor ◽  
Collagen Type 1

Tenocytes are mechanosensitive cells intimately adapting their expression profile and hence, their phenotype to their respective mechanomilieu. The immunolocalization and expression intensity of tenogenic, anabolic and catabolic markers in tenocytes in response to in vitro mechanical loading have not been monitored by immunohistochemical staining (IHC). Thus, we investigated the association between IHC intensities, different stimulation frequencies, and tenogenic metabolism using a versatile mechanical stretcher. Primary tenocytes obtained from murine Achilles tendons were transferred to poly(dimethylsiloxane) (PDMS) elastomeric chamber. Chambers were cyclically stretched by 5% in uniaxial direction at a variation of tensile frequency (1 or 2 Hz) for 3 h. After stretching, cell physiology, IHC intensities of tendon-related markers, and protein level of the angiogenesis marker vascular endothelial growth factor (VEGF) were evaluated. Cell proliferation in tenocytes stimulated with 1 Hz stretch was significantly higher than with 2 Hz or without stretch, while 2 Hz stretch induced significantly reduced cell viability and proliferation with microscopically detectable apoptotic cell changes. The amount of scleraxis translocated into the nuclei and tenomodulin immunoreactivity of tenocytes treated with stretch were significantly higher than of non-stretched cells. The collagen type-1 expression level in tenocytes stretched at 1 Hz was significantly higher than in those cultivated with 2 Hz or without stretching, whereas the matrix metalloproteinase (MMP)-1 and MMP-13 immunoreactivities of cells stretched at 2 Hz were significantly higher than in those stimulated with 1 Hz or without stretching. The secreted VEGF-protein level of tenocytes stretched at 2 Hz was significantly higher than without stretching. Our IHC findings consistent with cell physiology suggest that appropriate stretching can reproduce in vitro short-term tenogenic anabolic/catabolic conditions and allow us to identify an anabolic stretching profile.

P-glycoprotein plays a drug-efflux–independent role in augmenting cell survival in acute myeloblastic leukemia and is associated with modulation of a sphingomyelin-ceramide apoptotic pathway

Blood ◽  
2000 ◽  
Vol 95 (9) ◽  
pp. 2897-2904 ◽  
Author(s):  
Monica Pallis ◽  
Nigel Russell
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Apoptotic Cell ◽  
Patient Specific ◽  
Apoptosis Resistance ◽  
Reversal Agent ◽  
Apoptotic Pathway ◽  
Psc 833 ◽  
P Glycoprotein

P-glycoprotein (pgp), which is the product of the MDR1(multidrug resistance-1) gene, has an established role as a mediator of cytotoxic drug resistance in acute myeloid leukemia (AML). To study the role of pgp in mediating apoptosis resistance in AML cells deprived of serum and growth factors, apoptosis was quantified by flow cytometry using uptake of the dye 7-amino-actinomycin D (7-AAD) alongside low forward scatter. In pgp+ve primary AML samples, there was a significant increase in apoptosis in the presence of the pgp-specific antibody UIC2 (mean increase: 58%; range: 11%-95%; P < .05). Likewise, apoptosis in growth factor–deprived TF1 cells cultured for 30 hours increased 2.5-fold in the presence of 25 μg/mL UIC2. The pgp reversal agent PSC-833 (1 μmol/L) augmented in vitro apoptosis by a median of 52% in pgp+ve patient samples and to a comparable degree in 6 pgp−ve samples. To determine whether the sphingomyelin-ceramide (SM-ceramide) pathway of apoptosis occurs in AML blasts in response to cytotoxic drugs, cells were incubated with daunorubicin at the patient-specific IC30 (the concentration of daunorubicin that caused apoptotic cell death in 30% of cells) in the presence of the ceramide synthase inhibitor fumonisin B1, which inhibited apoptosis by 18%-81% (median: 40%). Exogenous SM failed to augment apoptosis induced by growth factor withdrawal in pgp+ve TF1 cells and was significantly more effective at augmenting apoptosis in pgp−ve patient blasts (median increase in cell death: 33%; range: 19%-88%) than in pgp+ve samples (median: 7%; range: 0%-27%;P = .028). Cellular accumulation of exogenous SM was associated with apoptosis and also occurred in nonapoptotic patient cells treated with PSC-833. However, this effect was not seen following treatment with the UIC2 antibody. These results indicate that pgp is able to exert a protective effect on AML cell viability and that this is associated with a reduced effect of exogenous SM on apoptosis. The pgp reversal agent PSC-833 acts, at least in part, by a pgp independent mechanism to alter SM distribution and to augment apoptosis induced in AML cells by serum and growth factor withdrawal.

Humanized anti-DEspR monoclonal antibody to improve overall survival in xenograft pancreatic peritoneal carcinomatosis nude rat model.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16262-e16262
Author(s):  
Christopher Gromisch ◽  
Matthew Stannard Gromisch ◽  
Mark Grinstaff ◽  
Victoria L.M. Herrera ◽  
Nelson Ruiz-Opazo
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Single Dose ◽  
Peritoneal Carcinomatosis ◽  
Rat Model ◽  
Median Overall Survival ◽  
Caspase 3 ◽  
Xenograft Tumor ◽  
Anoikis Resistance ◽  
Nude Rat

e16262 Background: Pancreatic adenocarcinoma (PDAC) with peritoneal carcinomatosis (PPC) has the worst median overall survival (mOS) among all PDAC metastasis. Novel therapeutic approaches are needed for PPC. The Dual Endothelin-1/VEGF-signal-peptide Receptor (DEspR) is a cell surface receptor which regulates PDAC tumor cell and cancer stem-like cell (CSC) anoikis resistance, tumorigenicity, and tumoral angiogenesis. To translate these findings into a novel anti-cancer therapy, we evaluated the efficacy, empirical safety, pharmacokinetics, and pharmacodynamics of a recombinant, humanized, anti-DEspR hinge-stabilized IgG4S228P monoclonal antibody, hu-6g8, in a PPC xenograft tumor nude rat model. Methods: We used a Panc1 CSC-derived xenograft tumor model of PPC developed via intraperitoneal injection of two million Panc1 CSCs functionally isolated for anoikis resistance. Isolated CSCs had variable DEspR expression, thus modeling CSC-heterogeneity. For efficacy studies, PPC-rats were randomized to receive a single intravenous injection of either 3mg/kg or 15mg/kg hu-6g8, 100mg/kg gemcitabine, or saline, given 3 weeks after CSC injection with palpable PPC tumors. Blood samples were collected to monitor for hematological adverse events (AEs) and vital organs were collected to evaluate for hu-6g8-induced apoptosis. Pharmacokinetics was assessed in a separate study cohort by sequential blood draws after rats received a single dose of 3 mg/kg or 15 mg/kg hu-6g8. In a 3rd cohort, pharmacodynamics were assessed by vital organ collection and immunohistochemistry after rats received either a single-iv injection of 3mg/kg hu-6g8 or IgG4 isotype control. Results: Single dose 15 mg/kg hu-6g8 treatment significantly improved median overall survival (189 days, n = 0.0007) with 3 mg/kg hu-6g8 being comparable to 100 mg/kg gemcitabine (92 vs 115 days, n = 0.62). No hematological AEs were observed in hu-6g8 treated rats, and there was no evidence of increased apoptosis by hu-6g8 in normal tissues by immunohistochemistry of activated Caspase-3. Hu-6g8 demonstrated an average elimination half-life of 46.1 hrs in a two-compartment model. Biodistribution of the antibody showed predominant uptake, albeit heterogenous, and induction of activated caspase 3+ apoptosis in the peritoneal tumors by 24-hours with minimal off-target binding. Conclusions: Treatment with monoclonal hu-6g8 significantly improved survival in a model of PCC with excellent tumor specificity and minimal off-target effect.

scholarly journals Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal malignancy: initial experience of the first program in the Baltic countries

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rokas Račkauskas ◽  
Augustinas Baušys ◽  
Martynas Lukšta ◽  
Jonas Jurgaitis ◽  
Marius Paškonis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peritoneal Carcinomatosis ◽  
Cancer Patients ◽  
Postoperative Morbidity ◽  
Metastatic Cancer ◽  
Objective Assessment ◽  
Peritoneal Metastases ◽  
Initial Experience ◽  
Invasive Approach ◽  
The Baltic

Abstract Background Peritoneal malignancies include primary and metastatic cancer of the peritoneal cavity. The most common origin for peritoneal metastasis is ovarian, gastric, and colorectal cancers. Irrespective of the origin, peritoneal metastases represent the advanced disease and are associated with poor long-term outcomes. The minimally invasive approach of pressurized intraperitoneal aerosol chemotherapy (PIPAC) allows repeated applications and objective assessment of tumor response by comparing histological samples. This study aimed to investigate the initial experience with PIPAC in the Baltic region. Methods All patients who underwent PIPAC at Vilnius University Hospital Santaros Klinikos between 2015 and 2020 were included in this retrospective study. The primary outcome of the study was overall survival (OS) in patients with peritoneal carcinomatosis treated by PIPAC. The secondary outcomes included postoperative morbidity; peritoneal carcinomatosis index (PCI) and ascites reduction after treatment by PIPAC. Results In total, 15 patients underwent 34 PIPAC procedures. PIPAC-related intraoperative and postoperative morbidity occurred in 3 (8.8%) of 34 procedures. Following PIPAC, the median PCI decreased from 8 (4; 15) to 5 (1; 16) in GC patients, although, the difference failed for significance, p = 0.581. In OC patients, PCI after PIPAC remained stable. Median overall survival after PIPAC procedure was 25 (95% CI 5–44) months. Ovarian cancer patients (22; 95% CI 12–44 months) had significantly higher OS, compared to gastric cancer patients (8; 95% CI 4–16 months), p = 0.018. Conclusions PIPAC is safe and feasible for patients with gastric and ovarian cancers peritoneal metastases.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

scholarly journals An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marisa Nacke ◽  
Emma Sandilands ◽  
Konstantina Nikolatou ◽  
Álvaro Román-Fernández ◽  
Susan Mason ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Cellular Responses ◽  
Signalling Pathways ◽  
External Signal ◽  
Phosphoinositide Metabolism ◽  
Invasion And Metastasis ◽  
3 Dimensional

AbstractThe signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P3-AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.

scholarly journals Important Role for Phylogenetically Invariant PP2Acα Active Site and C-Terminal Residues Revealed by Mutational Analysis in Saccharomyces cerevisiae

Genetics ◽  
2000 ◽  
Vol 156 (1) ◽  
pp. 21-29 ◽  
Author(s):  
David R H Evans ◽  
Brian A Hemmings
Keyword(s):  
Protein Interactions ◽  
Active Site ◽  
Protein Function ◽  
Mutational Analysis ◽  
Yeast Cells ◽  
Temperature Sensitive ◽  
Active Site Residues ◽  
Catalytic Function

Abstract PP2A is a central regulator of eukaryotic signal transduction. The human catalytic subunit PP2Acα functionally replaces the endogenous yeast enzyme, Pph22p, indicating a conservation of function in vivo. Therefore, yeast cells were employed to explore the role of invariant PP2Ac residues. The PP2Acα Y127N substitution abolished essential PP2Ac function in vivo and impaired catalysis severely in vitro, consistent with the prediction from structural studies that Tyr-127 mediates substrate binding and its side chain interacts with the key active site residues His-118 and Asp-88. The V159E substitution similarly impaired PP2Acα catalysis profoundly and may cause global disruption of the active site. Two conditional mutations in the yeast Pph22p protein, F232S and P240H, were found to cause temperature-sensitive impairment of PP2Ac catalytic function in vitro. Thus, the mitotic and cell lysis defects conferred by these mutations result from a loss of PP2Ac enzyme activity. Substitution of the PP2Acα C-terminal Tyr-307 residue by phenylalanine impaired protein function, whereas the Y307D and T304D substitutions abolished essential function in vivo. Nevertheless, Y307D did not reduce PP2Acα catalytic activity significantly in vitro, consistent with an important role for the C terminus in mediating essential protein-protein interactions. Our results identify key residues important for PP2Ac function and characterize new reagents for the study of PP2A in vivo.

scholarly journals EP4 as a Negative Prognostic Factor in Patients with Vulvar Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1410
Author(s):  
Anna Buchholz ◽  
Aurelia Vattai ◽  
Sophie Fürst ◽  
Theresa Vilsmaier ◽  
Christina Kuhn ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factor ◽  
Vulvar Cancer ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Common Finding ◽  
Cancer Tissue ◽  
Vulvar Carcinoma ◽  
Tissue Samples

New prognostic factors and targeted therapies are urgently needed to improve therapeutic outcomes in vulvar cancer patients and to reduce therapy related morbidity. Previous studies demonstrated the important role of prostaglandin receptors in inflammation and carcinogenesis in a variety of tumor entities. In this study, we aimed to investigate the expression of EP4 in vulvar cancer tissue and its association with clinicopathological data and its prognostic relevance on survival. Immunohistochemistry was performed on tumor specimens of 157 patients with vulvar cancer treated in the Department of Obstetrics and Gynecology, Ludwig-Maximilian-University of Munich, Germany, between 1990 and 2008. The expression of EP4 was analyzed using the well-established semiquantitative immunoreactivity score (IRS) and EP4 expression levels were correlated with clinicopathological data and patients’ survival. To specify the tumor-associated immune cells, immunofluorescence double staining was performed on tissue samples. In vitro experiments including 5-Bromo-2′-Deoxyuridine (BrdU) proliferation assay and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromid (MTT) viability assay were conducted in order to examine the effect of EP4 antagonist L-161,982 on vulvar carcinoma cells. EP4 expression was a common finding in in the analyzed vulvar cancer tissue. EP4 expression correlated significantly with tumor size and FIGO classification and differed significantly between keratinizing vulvar carcinoma and nonkeratinizing carcinoma. Survival analysis showed a significant correlation of high EP4 expression with poorer overall survival (p = 0.001) and a trending correlation between high EP4 expression and shorter disease-free survival (p = 0.069). Cox regression revealed EP4 as an independent prognostic factor for overall survival when other factors were taken into account. We could show in vitro that EP4 antagonism attenuates both viability and proliferation of vulvar cancer cells. In order to evaluate EP4 as a prognostic marker and possible target for endocrinological therapy, more research is needed on the influence of EP4 in the tumor environment and its impact in vulvar carcinoma.

Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Bharti Patel ◽  
Subrata Mishra ◽  
Indira K. Priyadarsini ◽  
Sirisha L. Vavilala
Keyword(s):  
Quorum Sensing ◽  
Respiratory Tract ◽  
Protein Function ◽  
Docking Studies ◽  
Klebsiella Pneumonia ◽  
Potential Candidate ◽  
In Silico Studies ◽  
Specific Proteins ◽  
Tract Infections

Abstract Bacteria are increasingly relying on biofilms to develop resistance to antibiotics thereby resulting in their failure in treating many infections. In spite of continuous research on many synthetic and natural compounds, ideal anti-biofilm molecule is still not found thereby warranting search for new class of molecules. The current study focuses on exploring anti-biofilm potential of selenocystine against respiratory tract infection (RTI)-causing bacteria. Anti-bacterial and anti-biofilm assays demonstrated that selenocystine inhibits the growth of bacteria in their planktonic state, and formation of biofilms while eradicating preformed-biofilm effectively. Selenocystine at a MIC50 as low as 42 and 28 μg/mL effectively inhibited the growth of Klebsiella pneumonia and Pseudomonas aeruginosa. The antibacterial effect is further reconfirmed by agar cup diffusion assay and growth-kill assay. Selenocystine showed 30–60% inhibition of biofilm formation in K. pneumonia, and 44–70% in P. aeruginosa respectively. It also distorted the preformed-biofilms by degrading the eDNA component of the Extracellular Polymeric Substance matrix. Molecular docking studies of selenocystine with quorum sensing specific proteins clearly showed that through the carboxylic acid moiety it interacts and inhibits the protein function, thereby confirming its anti-biofilm potential. With further validation selenocystine can be explored as a potential candidate for the treatment of RTIs.

Sign in / Sign up

Export Citation Format

Share Document