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Tumor Discovery Role of honokiol in combination therapy

and vascular endothelial growth factor signaling. Our tumor clones. Acquired resistance is primarily driven by
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research demonstrated that honokiol, administered alone the complex and adaptive nature of tumor architecture.
or in combination with CsA, effectively inhibits these Tumor cells dynamically remodel their microenvironment
cancer-promoting pathways in RCC models. Moreover, through physical and biochemical mechanisms, promoting
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honokiol’s anti-inflammatory effects may allow for dose immune evasion, migration, invasion, and resistance to
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reduction of CsA without compromising graft survival, apoptosis. These adaptive changes create barriers to
potentially reducing its oncogenic side effects. effective drug delivery and foster the survival of drug-
resistant cancer cell populations. Combination therapies
6.2. Rapamycin and honokiol (Table 1) have emerged as a more effective strategy than
Rapamycin (sirolimus), an mTOR inhibitor, is frequently single-agent treatments, as they simultaneously target
employed to prevent organ rejection, particularly in renal multiple oncogenic pathways and enhance tumor cell
transplantation. While rapamycin possesses inherent eradication. Several combination regimens have already
anti-tumor activity, prolonged treatment can activate gained approval and are in clinical use, although further
compensatory survival pathways. Specifically, sustained improvements in efficacy, safety, and tolerability are still
rapamycin exposure relieves the negative feedback loop on needed. 81-83
AKT through inhibition of S6-kinase, potentially promoting In this context, drug repurposing has gained traction
tumor growth through PI3K-mTOR signaling. 75,76 as a viable strategy to reduce drug development costs
Sabarwal et al. explored the therapeutic potential and accelerate the translation of therapies into clinical
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of combining honokiol with rapamycin in post- practice. Natural compounds, including plant-derived
transplantation cancer models. This combination effectively bioactive molecules, have been extensively studied for
inhibited the c-MET-driven proliferation of renal cancer their anticancer potential. Honokiol, in particular, has
cells. c-MET is a RTK commonly overexpressed in RCC demonstrated potent anticancer activity across various
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and linked to tumor growth and metastasis. In addition, the malignancies, with additional preventive benefits.
combination downregulated programmed death-ligand 1, Notably, honokiol has shown the ability to sensitize therapy-
a key immune checkpoint molecule that facilitates tumor resistant cancer cells when used in combination with other
immune evasion. 26 conventional and targeted treatments. 29,36,38,42,49,53,59,60 Pre-
clinical studies from our laboratory have further confirmed
In a murine model of post-transplant renal cancer, the the therapeutic efficacy of honokiol in both cancer and
honokiol and rapamycin combination prolonged allograft post-transplantation settings. However, to fully elucidate
survival and significantly inhibited tumor growth. its clinical potential, more in-depth investigations are
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Mechanistically, this therapy modulated the expression warranted, including comprehensive pre-clinical studies
of tumor-promoting regulators such as Carabin and to fully evaluate the potential of honokiol as a treatment
Rubicon, induced autophagic and apoptotic cell death, option.
and reduced the expression of the RTK AXL, reported
to be overexpressed in various cancer types. Notably, Acknowledgments
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the combination also suppressed the expression of heme
oxygenase-1, a cytoprotective enzyme implicated in We thank Sudevi Sarkar Ghosh and Anisha Tarafder Dev
therapeutic resistance. These findings highlight honokiol’s for reading the manuscript.
potential as a novel adjunct therapy to mitigate post- Funding
transplant cancer risk while preserving graft survival.
A.S. acknowledges the Dana-Farber/Harvard Cancer
7. Conclusion Centre (DF/HCC), Kidney Cancer SPORE, Career
Therapeutic resistance remains one of the most significant Enhancement Award (CEP) 5P50CA101942-18 subaward.
obstacles to effective cancer treatment, contributing to S.P. acknowledges the National Institutes of Health Grants
disease progression and treatment failure. In response, (RO1 CA193675 and RO1 CA222355).
numerous therapeutic strategies have been developed Conflict of interest
to overcome this challenge. These include novel targeted
therapies such as SMIs of RTKs, immune checkpoint The authors declare they have no competing interests.
inhibitors, and mAbs designed to specifically target
resistant cancer subtypes. While these agents often elicit Author contributions
promising initial responses, they frequently lead to the Conceptualization: Soumitro Pal, Akash Sabarwal
emergence of more aggressive and therapy-resistant Funding acquisition: Soumitro Pal, Akash Sabarwal

Volume 4 Issue 2 (2025) 49 doi: 10.36922/td.8152