scholarly journals Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Antonín Brisuda ◽  
James C. S. Ho ◽  
Pancham S. Kandiyal ◽  
Justin T-Y. Ng ◽  
Ines Ambite ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Oleic Acid ◽  
Tumor Cells ◽  
Recurrence Rates ◽  
Acid Complex ◽  
Tumoricidal Activity ◽  
Peptide Motifs ◽  
Helical Peptide ◽  
Alpha Helical Peptide ◽  
Alpha Lactalbumin

AbstractPartially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.

scholarly journals Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4336
Author(s):  
Katherine E. Chetta ◽  
Joseph L. Alcorn ◽  
John E. Baatz ◽  
Carol L. Wagner
Keyword(s):  
Oleic Acid ◽  
Human Milk ◽  
Preterm Infants ◽  
Frozen Storage ◽  
Lipid Complex ◽  
Acid Complex ◽  
Very Preterm Infants ◽  
Very Preterm ◽  
Milk Casein ◽  
Alpha Lactalbumin

Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET’s possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET’s discovery, formation and bioactive benefits will be reviewed.

Behaviour of oleic acid-depleted bovine alpha-lactalbumin made LEthal to tumor cells (BAMLET)

2016 ◽  
Vol 12 (6) ◽  
pp. 1871-1880 ◽  
Author(s):  
Mehboob Hoque ◽  
Jyoti Gupta ◽  
Gulam Rabbani ◽  
Rizwan Hasan Khan ◽  
M. Saleemuddin
Keyword(s):  
Oleic Acid ◽  
Tumor Cells ◽  
Alpha Lactalbumin

Oleic acid (OA) complexes of human alpha-lactalbumin (α-LA) and several other proteins are effective in the killing of a variety of tumor cells.

scholarly journals Hyperthermia as Adjunct to Intravesical Chemotherapy for Bladder Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Richmond A. Owusu ◽  
Michael R. Abern ◽  
Brant A. Inman
Keyword(s):  
Bladder Cancer ◽  
Tumor Cells ◽  
Recurrence Risk ◽  
Intravesical Chemotherapy ◽  
Temperature Sensitive ◽  
Hyperthermia Treatment ◽  
Recurrence Rates ◽  
Benign Tissue ◽  
Concurrent Use ◽  
Immune Mediated

Nonmuscle invasive bladder cancer remains a very costly cancer to manage because of high recurrence rates requiring long-term surveillance and treatment. Emerging evidence suggests that adjunct and concurrent use of hyperthermia with intravesical chemotherapy after transurethral resection of bladder tumor further reduces recurrence risk and progression to advanced disease. Hyperthermia has both direct and immune-mediated cytotoxic effect on tumor cells including tumor growth arrest and activation of antitumor immune system cells and pathways. Concurrent heat application also acts as a sensitizer to intravesical chemotherapy agents. As such the ability to deliver hyperthermia to the focus of tumor while minimizing damage to surrounding benign tissue is of utmost importance to optimize the benefit of hyperthermia treatment. Existing chemohyperthermia devices that allow for more localized heat delivery continue to pave the way in this effort. Current investigational methods involving heat-activated drug delivery selectively to tumor cells using temperature-sensitive liposomes also offer promising ways to improve chemohyperthermia efficacy in bladder cancer while minimizing toxicity to benign tissue. This will hopefully allow more widespread use of chemohyperthermia to all bladder cancer patients, including metastatic bladder cancer.

scholarly journals Combination of GP88 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Is an Independent Prognostic Factor for Bladder Cancer Patients

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1796
Author(s):  
Markus Eckstein ◽  
Verena Lieb ◽  
Rudolf Jung ◽  
Danijel Sikic ◽  
Katrin Weigelt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Factor ◽  
Tumor Cells ◽  
Immune Cells ◽  
Potential Candidate ◽  
Poor Prognostic Factor ◽  
Risk Of Death ◽  
Increased Risk ◽  
Muscle Invasive ◽  
Disease Specific

Urothelial bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide and accounts for approximately 3% of global cancer diagnoses. We are interested in prognostic markers that may characterize tumor cells (TCs) and immune cells (ICs) and their relationship in BCa. A potential candidate marker that meets these criteria is progranulin (GP88), which is expressed separately in TCs and ICs. We analyzed GP88 expression by immunohistochemistry (IHC) in 196 muscle-invasive BCa samples using a tissue microarray. The immunoreactive score for GP88 staining in TCs and the percentage of GP88-positive ICs was determined. An easy cutoff for the staining status of TCs (positive vs. negative) and ICs (0% vs. >0%) and, more generally, negative vs. positive GP88 staining could be applied. We detected 93 patients (47.4%) and 92 patients (46.9%) with GP88-positive TCs or ICs, respectively. The IHC results were correlated with clinicopathological and survival data. Positive GP88 staining in TCs appeared to be an independent poor prognostic factor for disease-specific survival (DSS) (RR (relative risk) = 1.74; p = 0.009) and recurrence-free survival (RFS) (RR = 1.92; p = 0.002). In contrast, negative GP88 staining in ICs was an independent negative predictor for overall survival (OS) (RR = 2.18; p < 0.001), DSS (RR = 2.84; p < 0.001) and RFS (RR = 2.91; p < 0.001) in multivariate Cox’s regression analysis. When combining GP88 staining in TCs and ICs, a specific combination of GP88-positive TCs and GP88-negative ICs was associated with a 2.54-fold increased risk of death, a 4.21-fold increased risk of disease-specific death and a 4.81-fold increased risk of recurrence compared to GP88-negative TCs and GP88-positive ICs. In summary, GP88 positivity in TCs is a negative prognostic factor for DSS and RFS. In addition, GP88 positivity can mark ICs that are associated with a good prognosis (OS, DSS and RFS). The combination of GP88 staining in TCs and ICs appears to be a significant independent prognostic biomarker in muscle-invasive BCa.

901 Non-muscle invasive bladder cancer and circulating tumor cells: Individuation and prognostic value

2012 ◽  
Vol 11 (1) ◽  
pp. e901-e901a
Author(s):  
G.M. Busetto ◽  
R. Giovannone ◽  
G. Antonini ◽  
M. Di Placido ◽  
A. Petracca ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Prognostic Value ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

scholarly journals Interaction of Lactoferrin with Unsaturated Fatty Acids: In Vitro and In Vivo Study of Human Lactoferrin/Oleic Acid Complex Cytotoxicity

Materials ◽  
2021 ◽  
Vol 14 (7) ◽  
pp. 1602
Author(s):  
Anna Elizarova ◽  
Alexey Sokolov ◽  
Valeria Kostevich ◽  
Ekaterina Kisseleva ◽  
Evgeny Zelenskiy ◽  
...  
Keyword(s):  
Oleic Acid ◽  
Structural Changes ◽  
Unsaturated Fatty Acids ◽  
Structural Features ◽  
Control Group ◽  
Acid Complex ◽  
Hepatoma 22A ◽  
Constitutive Parameters

As shown recently, oleic acid (OA) in complex with lactoferrin (LF) causes the death of cancer cells, but no mechanism(s) of that toxicity have been disclosed. In this study, constitutive parameters of the antitumor effect of LF/OA complex were explored. Complex LF/OA was prepared by titrating recombinant human LF with OA. Spectral analysis was used to assess possible structural changes of LF within its complex with OA. Structural features of apo-LF did not change within the complex LF:OA = 1:8, which was toxic for hepatoma 22a cells. Cytotoxicity of the complex LF:OA = 1:8 was tested in cultured hepatoma 22a cells and in fresh erythrocytes. Its anticancer activity was tested in mice carrying hepatoma 22a. In mice injected daily with LF-8OA, the same tumor grew significantly slower. In 20% of animals, the tumors completely resolved. LF alone was less efficient, i.e., the tumor growth index was 0.14 for LF-8OA and 0.63 for LF as compared with 1.0 in the control animals. The results of testing from 48 days after the tumor inoculation showed that the survival rate among LF-8OA-treated animals was 70%, contrary to 0% rate in the control group and among the LF-treated mice. Our data allow us to regard the complex of LF and OA as a promising tool for cancer treatment.

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