Partially 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.

• MeSH
• apoptóza účinky léků   MeSH
• endocytóza účinky léků   MeSH
• konformace proteinů MeSH
• kyseliny olejové chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory močového měchýře farmakoterapie   genetika   patologie   MeSH
• peptidy chemie   farmakologie   terapeutické užití   MeSH
• placebo MeSH
• protonová magnetická rezonanční spektroskopie MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• sekvence aminokyselin MeSH
• stanovení cílového parametru MeSH
• termodynamika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• kyseliny olejové MeSH
• peptidy MeSH
• placebo MeSH

The protein-lipid complex alpha1-oleate, derived from HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells), is identified as a molecular entity with significant therapeutic potential. Structural characterization of the complex and results of a successful placebo-controlled clinical trial are presented.

• Klíčová slova
• Novel cancer therapy, bladder cancer, low toxicity, peptide-oleate complex, protein folding,
• Publikační typ
• časopisecké články MeSH

Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.

• Klíčová slova
• Alpha1-oleate, bladder cancer therapy, dose escalation, lack of toxicity,
• MeSH
• aplikace intravezikální MeSH
• králíci MeSH
• kyselina olejová aplikace a dávkování   chemie   toxicita   MeSH
• laktalbumin aplikace a dávkování   chemie   toxicita   MeSH
• lidé MeSH
• močový měchýř účinky léků   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie transplantace   MeSH
• nádory močového měchýře farmakoterapie   patologie   MeSH
• protinádorové látky aplikace a dávkování   chemie   toxicita   MeSH
• screeningové testy protinádorových léčiv MeSH
• testy subchronické toxicity MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina olejová MeSH
• laktalbumin MeSH
• protinádorové látky MeSH

HER2-positive breast cancer is an aggressive subtype that typically responds poorly to standard chemotherapy. To design an anticancer drug selective for HER2-expressing breast cancer, a PtIV prodrug with axial oleate and cinnamate ligands was synthesized. We demonstrate its superior antiproliferative activity in monolayer and 3D spheroid models; the antiproliferative efficiency increases gradually with increasing expression of HER2. The results also suggest that the released PtII compound inhibits the proliferation of cancer cells by a DNA-damage-mediated mechanism. Simultaneously, the released oleic and cinnamic acid can effectively inhibit HER2 expression. To our knowledge, this is the first platinum-based complex inhibiting HER2 expression that does not contain protein or peptide. Moreover, this PtIV prodrug is capable of overcoming the resistance of cancer stem cells (CSCs), inducing death in both CSCs and differentiated cancer cells. Thus, the results substantiate our design strategy and demonstrate the potential of this approach for the development of new, therapeutically relevant compounds.

• Klíčová slova
• breast cancer, medicinal chemistry, metals in medicine, platinum, prodrugs,
• MeSH
• buněčná diferenciace účinky léků   MeSH
• cinnamáty chemie   farmakologie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• kyselina olejová chemie   farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• platina chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• receptor erbB-2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• screeningové testy protinádorových léčiv MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cinnamáty MeSH
• ERBB2 protein, human MeSH Prohlížeč
• komplexní sloučeniny MeSH
• kyselina olejová MeSH
• platina MeSH
• protinádorové látky MeSH
• receptor erbB-2 MeSH