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Tumor Discovery Role of honokiol in combination therapy

1. Introduction

Therapeutic resistance is a significant barrier to achieving
1
durable responses in cancer treatment. Despite considerable
advances in the development of chemotherapies, targeted
therapies, and monoclonal antibodies (mAbs), resistance,
both intrinsic and acquired, continues to drive treatment
2
failure, tumor progression, and poor patient prognosis.
Conventional chemotherapeutic agents, such as paclitaxel
and doxorubicin, have long been the cornerstone of cancer
management. However, their non-specific cytotoxicity
often results in dose-limiting toxicities and the emergence
of resistant tumor clones. 3,4
The introduction of molecular targeted therapies,
particularly receptor tyrosine kinase (RTKs) inhibitors,
marked a pivotal advancement in precision oncology.
5
Drugs, such as cabozantinib, lapatinib, erlotinib, and Figure 1. The figure illustrates the diverse biological activities of
osimertinib, selectively inhibit key oncogenic drivers honokiol with broad therapeutic potential. Adapted and modified from
our previously published article (Phytochemistry Reviews, 2025, Solanki
in various malignancies. However, resistance to these et al. ), with copyright permission and license obtained from Springer
18
agents often develops through secondary mutations, Nature (Licence Number: 5986590534892).
bypass signaling, and activation of compensatory
pathways. Similarly, mAbs such as cetuximab have can paradoxically promote tumorigenesis by suppressing
transformed the treatment landscape of many cancers. immune surveillance and activating oncogenic pathways. 21,22
Nevertheless, immune escape mechanisms and tumor Honokiol, when combined with these immunosuppressants,
microenvironment factors frequently limit their long- has demonstrated efficacy in mitigating cancer-promoting
term efficacy. signals while maintaining graft viability in pre-clinical
Combination therapies are increasingly recognized as a models. This review aims to summarize the present pre-
strategic approach to overcoming therapeutic resistance. clinical evidence on honokiol, focusing on its role in
6,7
In this context, bioactive natural compounds have gained combination therapies for cancer treatment, where its
significant interest due to their multitargeted actions, dual anti-inflammatory and anti-tumor effects may offer
favorable safety profiles, and the ability to synergize with significant benefits.
standard therapies. 8-14 Honokiol, a biphenolic compound
derived from the bark and leaves of the Magnolia species, 2. Combination therapies with honokiol
has demonstrated a broad spectrum of pharmacological Combination therapy involving honokiol has been
properties, including anti-cancer, anti-inflammatory, extensively investigated in pre-clinical studies (Figure 2).
antioxidant, and neuroprotective effects (Figure 1). 15-18 Both in vitro and in vivo research have demonstrated
Importantly, honokiol has shown the potential to resensitize that honokiol can enhance the efficacy of chemotherapy,
resistant cancer cells to chemotherapeutic agents and radiation therapy, and targeted therapies across various
targeted therapies, while enhancing the efficacy of mAbs. cancers, including renal, oral, breast, lung, pancreatic, and
19
Mechanistically, honokiol modulates several key oncogenic colorectal cancer. 23-26 These studies suggest that honokiol
and survival pathways, including phosphoinositide 3-kinase could improve treatment outcomes when combined with
(PI3K)/protein kinase B (AKT), mitogen-activated protein conventional therapies.
kinase (MAPK)/extracellular signal-regulated kinase, signal
transducer and activator of transcription 3 (STAT3), and 2.1. Cisplatin and honokiol
nuclear factor kappa B (NF-κB), and can reverse epithelial- Cisplatin, a widely used chemotherapy drug, is effective
mesenchymal transition, inhibit angiogenesis, and restore against cancers, such as ovarian, bladder, lung, and
immune surveillance. 20 testicular cancer. It damages DNA in cancer cells,
27
In addition to its role in restricting cancer cell preventing their division and proliferation. However,
proliferation, honokiol has emerged as a promising cisplatin’s clinical use is limited by side effects such as
candidate for preventing post-transplantation malignancies. nausea, kidney damage, hearing loss, and nerve toxicity.
Immunosuppressive agents, such as cyclosporin A and To overcome these limitations, cisplatin is often used in
rapamycin, commonly used to prevent graft rejection, combination with other agents.

Volume 4 Issue 2 (2025) 43 doi: 10.36922/td.8152