A molecular complex of bovine milk protein and oleic acid selectively kills cancer cells <i>in vitro</i> and inhibits tumour growth in an orthotopic rat bladder tumour model
Bibliographic record
Abstract
UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Novel intravesical therapies are needed for superficial bladder cancer that reduce the risk of infection associated with Bacillus Calmette-Guérin (BCG) and further destabilization of the urothelium associated with cytotoxic chemotherapy. Experimental therapies to date have included photodynamic therapy, oncolytic viruses, gene therapy (antisense oligonucleotides and silencing RNA), cytokine therapy, death receptor agonists (tumour-necrosis-factor-related apoptosis-inducing ligand and anti-DR5 monoclonal antibody), naturally occurring substances (curcumin and deguelin) and human α-lactalbumin made lethal to tumour cells (HAMLET). HAMLET, a natural occurring product in milk, induces apoptosis in urothelial cancer cells but has limitations in clinical application because of its human source. A previous study in patients with bladder cancer has demonstrated that intravesical HAMLET (daily for 5 days before tumour resection) caused selective apoptotic tumour cell death. BAMLET, the bovine equivalent of HAMLET, is a complex of bovine α-lactalbumin and oleic acid (bLAC) that has been shown in vitro to accumulate in the endolysosomal compartment of tumour cells and induce leakage of lysosomal cathepsins into the cytosol followed by activation of the pro-apoptotic protein Bax. This is the first in vivo study to show that BAMLET (bLAC) induces apoptosis in urothelial cancer cells and controls the growth of high risk urothelial cancer in a syngeneic rat orthotopic model. This same bladder cancer model system has been used to test other novel therapies, including BCG, and therefore provides a relative comparison of its effectiveness with other intravesical therapies. OBJECTIVE: To investigate the efficacy of a complex of bovine α-lactalbumin and oleic acid (bLAC) to kill urothelial cancer cells in vitro and inhibit tumour growth and progression in a high risk bladder tumour model. MATERIALS AND METHODS: The cytotoxicity of bLAC to a large panel of urothelial cell cancer (UCC) cells was tested by the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay, using bLA, the folded α-lactalbumin without oleic acid, as a control. The mechanism of bLAC-inducing cell death was evaluated by annexin V staining, TUNEL (terminal deoxynucleotidyl transferase mediated nick end labelling) assay and sub-G1 DNA analysis. The selective bLAC cytotoxicity was examined using multicellular spheroids consisting of UCC and non-transformed fibroblasts. Rats bearing orthotopic tumour received intravesical instillations (twice weekly, for 3 weeks) of bLAC, bLA, BCG or saline, starting 6 days after UCC (AY-27) cell inoculation. Animals were monitored for survival, toxicity and tumour growth control. RESULTS: A dose-dependent bLAC-inducing apoptotic-like cell death was shown in UCC cells tested, including cells refractory to classic apoptosis-inducing agents, whereas bLA showed little cytotoxicity. bLAC selectively destroyed cancer cells in spheroids. Intravesical bLAC therapy demonstrated marked reduction in tumour growth/progression and significantly prolonged animal survival vs saline instillations (P = 0.004, log-rank test) and showed comparable efficacy with BCG (standard) therapy. CONCLUSION: The findings identify bLAC as a new candidate for UCC therapy and suggests that topical administration of bLAC alone or with BCG to prevent progression of bladder cancer warrants further exploration.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".