Investigating the Antitumor Effects of α-Lactalbumin– Oleic Acid Complexes (HAMLET and BAMLET) in Colorectal Cancer: A Systematic Perspective

Abstract

Objectives: Recently, attention has turned toward naturally derived complexes such as HAMLET (Human α-lactalbumin Made Lethal to Tumor Cells) and BAMLET (Bovine α-lactalbumin Made Lethal to Tumor Cells) due to their selective cytotoxicity and promising mechanisms of action. In this study, we aimed to systematically review the effect of HAMLET and BAMLET on colorectal cancer (CRC).

Methods: PubMed, Scopus, Web of Science, and Embase were searched for studies published between 2020–2025, with one 2006 study included for its unique mechanistic insights. The search combined specific keywords and MeSH terms related to HAMLET, BAMLET, colorectal cancer, antitumor activity, and signaling pathways, using Boolean operators. After removing duplicates and applying predefined inclusion and exclusion criteria, six eligible original studies (in vitro, in vivo, and xenograft models) were included.

Results: Both HAMLET and BAMLET demonstrated cytotoxic effects against CRC cells via diverse mechanisms such as autophagy inhibition, lysosomal membrane permeabilization, mitochondrial dysfunction, and modulation of β-catenin and CK1α signaling. BAMLET notably exhibited synergistic effects with 5-fluorouracil and contributed to reduced tumor growth in murine models. HAMLET’s efficacy varied depending on KRAS/BRAF mutation status and mitochondrial resilience. Importantly, no significant toxicity was observed in healthy non-cancerous cells across the studies.

Conclusion: These findings suggest that HAMLET and BAMLET represent viable adjuncts to standard CRC therapies, offering tumor-specific mechanisms with minimal side effects. Further exploration of their molecular interactions and clinical potential could enhance combination strategies and help overcome therapeutic resistance in CRC treatment.