Beta-sheet-specific interactions with heat shock proteins define a mechanism of delayed tumor cell death in response to HAMLET

Nadeem, Aftab; Ho, James C. S.; Tran, Tuan Hiep; Paul, Sanchari; Granqvist, Victoria; Despretz, Nadege; Svanborg, Catharina

doi:10.1016/j.jmb.2019.05.007

Cited by 10 publications

(7 citation statements)

References 36 publications

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“…In the second phase of the study, a median reduction of 82% in lesion volume was observed [ 277 ]. Tumor cell surface heat shock proteins (HSPs) bind the β-sheet domain of α-LA and activate a temporarily protective loop, involving vesicular uptake and lysosomal accumulation [ 278 ]. Later, HAMLET destroys lysosomal membrane integrity, and HAMLET release kills the remaining tumor cells.…”

Section: Anti-tumorigenic Activities Of α-Lactalbuminmentioning

confidence: 99%

α-Lactalbumin, Amazing Calcium-Binding Protein

Permyakov

2020

Biomolecules

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α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4–5), Ca2+-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the lactating mammary gland. The protein possesses a single strong Ca2+-binding site, which can also bind Mg2+, Mn2+, Na+, K+, and some other metal cations. It contains several distinct Zn2+-binding sites. Physical properties of α-LA strongly depend on the occupation of its metal binding sites by metal ions. In the absence of bound metal ions, α-LA is in the molten globule-like state. The binding of metal ions, and especially of Ca2+, increases stability of α-LA against the action of heat, various denaturing agents and proteases, while the binding of Zn2+ to the Ca2+-loaded protein decreases its stability and causes its aggregation. At pH 2, the protein is in the classical molten globule state. α-LA can associate with membranes at neutral or slightly acidic pH at physiological temperatures. Depending on external conditions, α-LA can form amyloid fibrils, amorphous aggregates, nanoparticles, and nanotubes. Some of these aggregated states of α-LA can be used in practical applications such as drug delivery to tissues and organs. α-LA and some of its fragments possess bactericidal and antiviral activities. Complexes of partially unfolded α-LA with oleic acid are cytotoxic to various tumor and bacterial cells. α-LA in the cytotoxic complexes plays a role of a delivery carrier of cytotoxic fatty acid molecules into tumor and bacterial cells across the cell membrane. Perhaps in the future the complexes of α-LA with oleic acid will be used for development of new anti-cancer drugs.

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Section: Anti-tumorigenic Activities Of α-Lactalbuminmentioning

confidence: 99%

α-Lactalbumin, Amazing Calcium-Binding Protein

Permyakov

2020

Biomolecules

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“…Epirubicin achieves broad toxicity by intercalating DNA strands 21,23,29 . Acute effects on cell proliferation were therefore examined, using BrdU as a read out after 3 hours.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, Epirubicin generates free radicals that cause DNA damage and cell death. 14,15,18,22 Like Epirubicin and MMC, alpha1-oleate targets tumor cell nuclei and interacts with histones and spliceosome constituents, 23 suggesting a possible molecular basis for synergy with Epirubicin and MMC. In our study, alpha1-oleate alone or in combination with Epirubicin or MMC was shown to maintain a near healthy bladder phenotype long-term, suggesting the potential for efficient prevention of tumor progression using these approaches.…”

Section: Introductionmentioning

confidence: 99%

Long‐term prevention of bladder cancer progression by alpha1‐oleate alone or in combination with chemotherapy

Hien

Ambite

Wan

et al. 2023

Intl Journal of Cancer

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Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of nonmuscle invasive bladder cancer. Our study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least 4 weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression.Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and in vitro, alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer.

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“…HAMLET or BAMLET (human/bovine α-lactalbumin made lethal against tumor cells), the widely known anticancer agent, are formed as the lipoprotein complex [ 25 ]. 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] ].…”

Section: Introductionmentioning

confidence: 99%