Bladder cancer therapy without toxicity—A dose‐escalation study of alpha1‐oleate

Abstract

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.

An integrative approach leads to the discovery of a novel anti-leukemic peptide from human milk

“…Secondly, HAMLET (human alpha-lactalbumin made lethal to tumor cells), a protein-lipid complex that induces apoptosis-like death in tumor cells, was discovered from a human milk protein ( 37 ). Alpha1H (the alpha1 domain of α-lactalbumin in complex with oleic acid), which was further developed from HAMLET, has now entered the First-in-Human trial in patients with bladder cancer (clinicaltrials.gov identifier NCT03560479) ( 38 ). Thirdly, ACP has never been explored from human milk.…”

HMP-S7 Is a Novel Anti-Leukemic Peptide Discovered from Human Milk

“…Secondly, human alpha-lactalbumin made lethal to tumor cells (HAMLET), a protein-lipid complex that induces apoptosislike death in tumor cells, was discovered from a human milk protein [43]. Alpha1H (the alpha1 domain of α-lactalbumin in complex with oleic acid), which was further developed from HAMLET, has now entered the First-in-Human trial in patients with bladder cancer (clinicaltrials.gov identifier NCT03560479) [44]. Thirdly, ACPs have never been explored from human milk.…”

Drug-loaded oleic-acid grafted mesoporous silica nanoparticles conjugated with α-lactalbumin resembling BAMLET-like anticancer agent with improved biocompatibility and therapeutic efficacy

“…Since HAMLET was firstly identified from human milk in 1995, these anticancer agents have been extensively studied due to their noticeable ability to kill diverse cancers cells and negligible cytotoxicity to normal cells [ 26 , 27 ]. Notably, as α-lactalbumin is a major protein of natural dietary nutrient, HAMLET/BAMLET is regarded as extremely safe anticancer agent [ [28] , [29] , [30] , [31] ]. Nevertheless, the scale-up preparation of HAMLET/BAMLET may involve labor-intensive work which may be an obstacle for the practical applications.…”