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Tumor Discovery Role of honokiol in combination therapy

treatment precision, and minimizing damage to normal (RCC). Despite its clinical success, tumor resistance often
tissues. However, drug resistance and limited efficacy in develops, limiting its long-term benefit.
some patient populations are challenging. Recent studies from our laboratory investigated the
Honokiol, combined with mAbs, has shown the potential synergistic effects of cabozantinib and honokiol in RCC
to overcome these limitations by enhancing therapeutic models. The studies focused on the role of the c-MET RTK
responses and mitigating resistance mechanisms. For in cancer progression and resistance. Hyperactivation
example, cetuximab is an anti-epidermal growth factor of c-MET promotes cancer cell survival by activating
receptor (EGFR) monoclonal antibody approved for pathways that help them withstand oxidative stress,
treating head and neck squamous cell carcinoma (HNSCC) contributing to drug resistance. 26,57
and metastatic colorectal cancer. Despite its efficacy, Mechanistic investigations identified proteins such as
resistance to cetuximab frequently develops. Pearson et al. Rubicon and p62, which regulate autophagy and oxidative
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demonstrated that combining honokiol with cetuximab stress, along with the transcription factor nuclear factor
produced significant antiproliferative effects in cetuximab- erythroid 2-related factor 2, as key players in resistance. The
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resistant cancer cells. The combination downregulated combination of cabozantinib and honokiol significantly
the human epidermal growth factor receptor (HER) family inhibited RCC cell proliferation in vitro and reduced tumor
members and inhibited associated signaling pathways, growth in vivo in xenograft models. Moreover, this combination
including MAPK and AKT. Furthermore, honokiol reduced therapy decreased the expression of Rubicon, p62, and heme
the phosphorylation of DRP1 and levels of ROS, indicating oxygenase-1, reducing tumor vascular density. 57
altered mitochondrial function. The combination therapy
was also validated in cetuximab-resistant HNSCC patient- These findings highlight honokiol’s potential to enhance
derived xenograft models, where it led to a notable delay cabozantinib’s anti-tumor efficacy and offer a promising
in tumor growth and decreased activation of MAPK, AKT, strategy to overcome resistance in RCC treatment.
and DRP1 signaling, consistent with in vitro findings.
4.2. Lapatinib and honokiol
These results highlight honokiol’s potential to overcome
resistance to cetuximab and enhance the efficacy of mAb- Lapatinib is a dual tyrosine kinase inhibitor targeting
EGFR and HER2, primarily used to treat HER2-positive
based therapies. In addition, honokiol’s ability to modulate breast cancer. Despite its efficacy, resistance, and toxicity
key signaling pathways and counteract resistance
mechanisms supports its use as a promising adjunct in remain concerns in clinical practice.
combination therapies involving mAbs and other targeted Honokiol has demonstrated broad anticancer activity in
agents. various breast cancer cell lines, including estrogen receptor-
positive, estrogen receptor-negative, and drug-resistant
4. Honokiol in combination with small- lines (e.g., adriamycin- and tamoxifen-resistant cells). It
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molecule inhibitors (SMIs) induces G1-phase cell cycle arrest and caspase-dependent
apoptosis in a time- and dose-dependent manner. Notably,
SMIs play a central role in modern oncology, offering
targeted inhibition of signaling proteins and pathways HER2 knockdown increases cellular sensitivity to honokiol-
critical to tumor growth and survival. They effectively induced apoptosis in HER2-overexpressing cells.
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block RTKs, such as EGFR, mesenchymal-epithelial The combination of honokiol and lapatinib significantly
transition factor (MET), and vascular endothelial amplifies anti-tumor effects in HER2-overexpressing breast
growth factor receptors (VEGFR), intracellular signaling cancer models. Mechanistically, honokiol downregulates
mediators, such as MAPK kinase and PI3K, and apoptotic AKT phosphorylation and upregulates PTEN expression,
regulators, including B-cell lymphoma 2. However, resulting in suppression of the PI3K/AKT/mammalian
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challenges such as acquired resistance and toxicity limit target of rapamycin (mTOR) pathway, an essential driver
their long-term success. Honokiol has emerged as a of cancer cell survival and proliferation. These findings
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promising agent in combination with SMIs, enhancing support the potential of combining honokiol with lapatinib
their anti-tumor efficacy while helping to overcome as a novel strategy for HER2-positive breast cancer.
resistance and reduce side effects. 24,56-58
4.3. Imatinib and honokiol
4.1. Cabozantinib (XL-184) and honokiol Imatinib is a well-established targeted therapy for chronic
Cabozantinib is a multi-kinase inhibitor targeting myeloid leukemia and gastrointestinal stromal tumors.
c-MET, VEGFRs, and other RTKs and has demonstrated Despite its success, resistance and incomplete responses
significant efficacy in cancers such as renal cell carcinoma necessitate a combination approach.

Volume 4 Issue 2 (2025) 46 doi: 10.36922/td.8152