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A new variant of the human α-lactalbumin-oleic acid complex as an anticancer agent for chronic myeloid leukemia.

ABSTRACT: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells. Although there have been advancements in treatment, there is still a need to develop a biotherapeutic agent. A new variant of the human alpha-lactalbumin-oleic acid (HALOA) complex has been synthesized, which showed similarities with SNARE. The native α-LA was treated with EDTA to remove Ca²⁺ ions confirmed by ICP-OES and Arsenazo III to unfold and attain apo structure. The apo LA was mixed with OA in a specific ratio, leading to HALOA complex formation. The conformational state from native to complex was elucidated by circular dichroism (far; 190-260 nm and near; 260-340 nm UV-CD), which confirmed that the complex consists of a majority of turns and β-sheet structure. SDS-PAGE result showed the masking effect of OA on apo α-LA. In the lane of the complex, there was no band detected. However, 1-anilino-8-naphthalene sulfonate (ANS) dye has shown maximum fluorescence intensity with the complex because of the availability of hydrophobic patches, which was further validated by NMR spectroscopy indicating the masking effect of OA on the apo α-LA. The SNARE behavior of the complex (500 nm) has been confirmed by TEM. This new structural variant complex shows anti-tumor activity on chronic myeloid leukemia by targeting the IL-8, survivin, and induces apoptosis through DNA fragmentation, but not against normal cells. Overall, the formulated complex shows that SNARE-like behavior can be used as a promising anti-tumor agent with lower toxicity and maximum bioavailability.

SUBMITTER: Singh V

PROVIDER: S-EPMC8742887 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

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A new variant of the human α-lactalbumin-oleic acid complex as an anticancer agent for chronic myeloid leukemia.

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