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Tumor Discovery Role of honokiol in combination therapy

Wang et al. demonstrated that honokiol induces two T790M mutations in NSCLC. Despite its clinical success,
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distinct forms of cell death in leukemia cells: Paraptosis at lower resistance develops, often due to additional mutations such
concentrations (characterized by cytoplasmic vacuolization as C797S, posing a major therapeutic challenge. Honokiol
and endoplasmic reticulum swelling) and apoptosis at higher has shown promise in overcoming acquired resistance
concentrations. These processes may occur sequentially or in to osimertinib. In pre-clinical studies, the combination
parallel, depending on honokiol dosage. of honokiol and osimertinib synergistically reduced cell
In addition, honokiol disrupts leukemia cell adhesion viability and colony formation in osimertinib-resistant
to the extracellular matrix in a concentration-dependent NSCLC cell lines. This combination also significantly
manner, potentially reducing metastatic potential. enhanced apoptosis compared to either agent alone.
Sequential treatment administering honokiol before In mouse xenograft models harboring EGFR 19del,
imatinib exhibited synergistic effects, enhancing imatinib’s T790M, and C797S triple mutations, co-treatment with
therapeutic efficacy in K562 leukemia cells. 59 honokiol and osimertinib effectively suppressed tumor
These findings suggest that honokiol’s dual-mode progression. Importantly, the combination was well-
induction of cell death, combining apoptotic and non- tolerated, with no significant toxicity observed in the treated
apoptotic mechanisms, may offer a novel approach for mice. Mechanistic analyses revealed that the combination
improving imatinib responses in leukemia treatment. therapy inhibited phosphorylation of extracellular signal-
regulated kinase (ERK) 1/2 and promoted degradation of
4.4. Erlotinib and honokiol anti-apoptotic protein myeloid cell leukemia-1, leading to
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Erlotinib, an EGFR inhibitor, is widely used to treat HNSCC enhanced induction of apoptosis. These findings support
and NSCLC. However, its long-term efficacy is often further clinical evaluation of honokiol and its derivatives
limited by the development of resistance, necessitating as adjuvants to overcome osimertinib resistance in EGFR-
alternative therapeutic strategies. Leeman-Neill et al. mutant NSCLC.
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investigated honokiol as a potential therapeutic agent for 5. Honokiol as an anti-inflammatory agent
HNSCC, focusing on its ability to target EGFR signaling.
Honokiol inhibited tumor cell proliferation (half maximal Inflammation plays a dual role in disease development,
effective concentration: 3.3 – 7.4 μM), induced apoptosis, particularly in cancer. Chronic inflammation can be
and suppressed key EGFR downstream signaling pathways, pro-tumorigenic due to the sustained presence of pro-
including MAPK, AKT, and STAT3. In addition, honokiol inflammatory cytokines, which promote tumor cell
enhanced the efficacy of erlotinib, leading to significant proliferation, survival, angiogenesis, and metastasis.
tumor growth inhibition in vivo. 56 Conversely, acute inflammation can exert anti-tumorigenic
effects by enhancing immune surveillance, promoting
Another study further demonstrated honokiol’s
potential in inhibiting lung cancer cell growth, driven by tumor-associated antigen presentation, and influencing
EGFR deregulation. Honokiol at concentrations 2.5 – 7.5 immune cell polarization. Honokiol has been extensively
μM suppressed cell proliferation by up to 93% and induced studied for its potent anti-inflammatory properties,
apoptosis in 61% of EGFR-overexpressing bronchial cells. contributing to its anti-cancer effects. It inhibits the
It also downregulated phosphorylated EGFR, AKT, STAT3, production of key pro-inflammatory cytokines, including
and cell cycle-related proteins within 6 – 12 h of treatment. tumor necrosis factor-alpha, IL-1 beta, and IL-6, across
62-64
Interestingly, although honokiol exhibited weaker direct various cell types. In addition, honokiol attenuates the
EGFR tyrosine kinase binding compared to erlotinib, its activation of critical inflammatory signaling pathways,
overall antiproliferative and pro-apoptotic effects were particularly NF-κB, a key regulator of inflammation. By
stronger, suggesting inhibition of additional critical inhibiting protein kinase C and MAPKs, honokiol disrupts
survival pathways. Furthermore, honokiol sensitized phosphorylation events essential for inflammatory signaling
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erlotinib-resistant cells to erlotinib and significantly cascades. These properties make honokiol a compelling
reduced lung tumor size and multiplicity by 49% in mouse candidate for modulating tumor-associated inflammation
models. These findings suggest honokiol’s potential as both and enhancing the efficacy of anti-cancer therapies.
a monotherapy and an adjuvant strategy for overcoming 6. Post-transplantation cancer and the role
erlotinib resistance in EGFR-driven cancers. 60
of honokiol in its prevention
4.5. Osimertinib and honokiol Post-transplantation cancers are malignancies that develop
Osimertinib is a third-generation, Food and Drug in organ or hematopoietic stem cell transplant recipients,
Administration-approved EGFR inhibitor that targets EGFR- primarily due to prolonged immunosuppressive therapy

Volume 4 Issue 2 (2025) 47 doi: 10.36922/td.8152