The anticancer activity of Honokiol

Honokiol is a natural bioactive compound isolated from the Magnolia tree's bark, seed cones, and leaves, particularly Magnolia officinalis. It is a biphenolic compound known for its potent antioxidant, anti-inflammatory, and anticancer properties. Traditionally used in East Asian herbal medicine, honokiol has gained interest in modern research due to its broad-spectrum anticancer effects across various cancers.

Honokiol has shown anti-proliferative effects in hormone-resistant cancer cells, suggesting it can counter estrogenic effects. In combination with medications like metformin, honokiol demonstrates a capacity to reduce tumor growth in hormone-resistant cancer cells, indicating it may disrupt pathways that persist even in low-estrogen environments.

Mechanisms of Honokiol in Cancer Treatment

Induction of Ferroptosis: In colon cancer cells, honokiol induces ferroptosis by regulating GPX4 activity, an essential antioxidant defense mechanism. This leads to increased lipid peroxidation and cancer cell death. In acute myeloid leukemia (AML), honokiol enhances HMOX1 expression, further promoting ferroptosis.

Apoptosis via JAK/STAT Pathway Suppression: Honokiol reduces sphere formation and xenograft growth in oral cancer stem-like cells by downregulating the JAK/STAT pathway, inducing apoptosis and reducing cancer cell proliferation and resistance.

Downregulation of PD-L1 and Enhancement of Antitumor Effects: In renal cancer cells, honokiol downregulates PD-L1 expression, enhancing immune surveillance and improving the efficacy of mTOR inhibitors when used in combination, showcasing its potential in immunotherapy.

Inhibition of HIF-1α-Mediated Glycolysis: Honokiol targets HIF-1α, a key regulator of glycolysis in cancer cells, especially under hypoxic conditions typical of tumors. This inhibition disrupts the Warburg effect, decreasing glucose uptake, lactate production, and overall ATP levels, which slows down tumor growth in breast cancer.

Targeting Hormone-Resistant Pathways: In hormone-resistant breast cancer models, honokiol shows antiproliferative effects and effectively induces cell death when combined with metformin. This dual approach is promising for hormone-resistant breast cancer treatments, as honokiol modulates Bcl-2 and PARP expression.

Inhibition of Cancer Stem Cell (CSC) Pathways: By targeting cancer stem-like cells (CSCs), honokiol decreases tumor recurrence potential. Its inhibition of the Notch and Wnt/β-catenin pathways disrupts the self-renewal and survival mechanisms of CSCs in various cancers, potentially leading to improved outcomes in traditionally resistant cancers.

Synergistic Effects with Chemotherapeutics: Honokiol works independently and enhances the efficacy of other cancer treatments. Its ability to downregulate PD-L1 and improve immune responses makes it an ideal candidate for combination therapies, mainly used with chemotherapeutic agents targeting cancer cells through distinct mechanisms.​

References

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