HONOKIOL

Honokiol and its related compound magnolol originate from magnolia bark. Absorption is better than many similar natural compounds. Clinical trials are lacking, though there is recent case study of a clinical trial for GBM [brain cancer]. Interestingly the patient had over 50% relative survival increase with adjuvant use of liposomal honokiol following chemotherapy.

Two additional case studies were published from an integrative care clinic in Santa Rosa, CA in 2020, also using lipsomal honokiol via IV. Both in late stage prostate cancer and triple negative breast cancer the treatment gave a level of sustained effects for these patients lacking in conventional oncology alternatives. (see Examples)

Pre-clinical lab studies show a range of anti-cancer activity, including in breast, kidney and ovarian cancer lines, and enhanced the effects of tyrosine kinase inhibitor carbozantinib in kidney cancer cell lines

 

 

TYPICAL ABSORPTION LEVELS

10 – 30%

EXAMPLES OF IMPROVED OUTCOMES

YES
ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

NO

Highlighted Studies

To the best of our knowledge, this case study is the first report of the adjunctive use of honokiol in a patient with GBM, providing evidence of its possible beneficial effects. The patient in this case study was given honokiol at the first disease progression and obtained an overall survival of up to 15 months, which is considerably longer than 9.3 months in patients with recurrent GBM given bevacizumab . Notably, there were no severe side effects that led to treatment discontinuation. In pa...

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Importantly, there were no severe side effects that required treatment discontinuation. HNK-IV was well tolerated, which allowed for higher dosing compared with oral administration. This case study is the first report of the adjunctive use of HNK-IV in humans with solid tumors. The individual cases of the 2 patients demonstrated that HNK-IV may exhibit anticancer activity or may work additively or synergistically with other medications in drug-resistant/hormone-resistant tumors. The prelimina...

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In summary, our results demonstrate that HNK significantly inhibits EMT in breast cancer cells and reveal a novel mechanism by which HNK regulates Snail and Slug via downregulation of their protein translation…These observations suggest that the HNK might be able to be developed as a suitable therapeutic strategy for breast cancer metastasis

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Honokiol can markedly enhance the therapeutic effectiveness of cabozantinib and inhibit key target proteins, Rubicon, p62 and Nrf2, involved in acquired therapeutic resistance. Destabilization of Nrf2 can promote oxidative stress within the tumor to facilitate cancer cell death through increased apoptosis and autophagy.
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TABLE OF REFERENCES

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10324972/3.5Being a potent anticancer agent in various human tumors, honokiol remarkably inhibits tumor growth (20). Lip-HNK can induce lysosomal degradation of Hsp90 client proteins in gefitinib-resistant NSCLC cells (21). It also provides an effective approach to inhibit tumor growth in cisplatin-resistant human ovarian cancer (15). Lip-HNK induces ROS-mediated apoptosis and autophagic inhibition in medulloblastoma (22). Lip-HNK enhances the apoptosis of breast cancer cells induced by Adriamycin and inhibits the proliferation of breast cancer cells both in vitro and in vivo (23). Currently, Lip-HNK has entered phase I clinical trials for the treatment of GBM and other tumors.The patient in this case study was given honokiol at the first disease progression and obtained an overall survival of up to 15 months, which is considerably longer than 9.3 months in patients with recurrent GBM given bevacizumab (16). Notably, there were no severe side effects that led to treatment discontinuation. In particular, Lip-HNK did not cause hematologic toxicities such as neutropenia, anemia, or thrombocytopenia, which are common in chemotherapy-induced myelosuppression. Beyond a stable disease maintained during Lip-HNK treatment, it seemed that Lip-HNK did not markedly affect the efficacy of subsequent chemotherapies
https://journals.sagepub.com/doi/10.1177/15347354209226153.5This case study is the first report of the adjunctive use of HNK-IV in humans with solid tumors. The individual cases of the 2 patients demonstrated that HNK-IV may exhibit anticancer activity or may work additively or synergistically with other medications in drug-resistant/hormone-resistant tumors. The preliminary findings suggest that the use of HNK-IV as an adjunctive therapy could be safe and beneficial. Further investigation into the optimum formulation of HNK-IV and its use as adjunctive therapy in cancer patients is warranted.As noted previously, HNK is known to cross the blood-brain barrier15 and shown to have benefits in astrocytomas/glioblastomas.16 This may warrant additional clinical investigation for potential adjunctive use in the treatment of glioblastomas. Importantly, there were no severe side effects that required treatment discontinuation. HNK-IV was well tolerated, which allowed for higher dosing compared with oral administration.
https://www.sciencedirect.com/science/article/pii/S2213231723003464#sec31Together, the findings from this pre-clinical study suggest that cabozantinib + Honokiol combination can be a novel treatment strategy to inhibit c-Met-induced renal tumor growth and to promote oxidative stress-mediated tumor cell death. Honokiol can markedly enhance the therapeutic effectiveness of cabozantinib and inhibit key target proteins, Rubicon, p62 and Nrf2, involved in acquired therapeutic resistanceInterestingly, in this study, we found that cabozantinib + Honokiol combination treatment can markedly downregulate Rubicon, p62 and Nrf2 in RCC cell. Also, it significantly prevents the nuclear translocation of Nrf2. Thus, our findings suggest that that Honokiol can significantly facilitate cabozantinib-mediated renal cancer cell death through the inhibition of Rubicon-p62, destabilization of Nrf2 and increased oxidative stress.Screenshot from 2024-02-03 10-01-38
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496153/1We uncovered a novel mechanism by which honokiol inhibits invasion and migration of breast cancer cells, which involves enhanced expression and cytosolic localization of LKB1 and AMPK activation. We also demonstrated the requirement of LKB1 and AMPK in honokiol-mediated inhibition of migration and invasion of breast cancer cells. Our results thus provide new insight into the mechanisms by which honokiol, a promising anticancer agent, inhibits breast carcinogenesis.Intriguingly, we discovered that honokiol treatment increased the expression and cytoplasmic translocation of tumor-suppressor LKB1 in breast cancer cells. LKB1 knockdown inhibited honokiol-mediated activation of AMPK and, more important, inhibition of migration and invasion of breast cancer cells. Furthermore, honokiol treatment resulted in inhibition of breast tumorigenesis in vivo. Analysis of tumors showed significant increases in the levels of cytoplasmic LKB1 and phospho-AMPK in honokiol-treated tumors.Screenshot from 2024-02-23 13-53-27
https://www.nature.com/articles/s41401-019-0240-x/figures/41In addition, HNK-treated mice showed decreased Snail expression and increased E-cadherin expression in metastatic nodules. In conclusion, HNK inhibits EMT in the breast cancer cells by downregulating Snail and Slug protein expression at the mRNA translation level. HNK has potential as an integrative medicine for combating breast cancer by targeting EMT.These findings were consistent with previous reports that HNK inhibits the invasion and migration of breast cancer cells [16, 20]. As a major process underlying tumor metastasis, EMT is characterized by the loss of cell-cell adhesion and increased cell motility and invasion. We observed that HNK inhibited the motility of breast cancer cells. Consistently, HNK upregulated the epithelial marker E-cadherin and downregulated mesenchymal markers such as Snail, Slug, and vimentin in breast cancer cells.Screenshot from 2024-02-03 10-17-35
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793218/1In conclusion, we uncovered an inverse relationship between LKB1 and iPSC inducers—Oct4, Nanog and Sox2. We put forth HNK as a bioactive strategy to induce LKB1 and inhibit stem-like phenotype of breast cancer cells via reducing expression of iPSC inducers, in part, mediated by Stat3-inactivation. Our results thus demonstrate the integral role of a previously unrecognized crosstalk between HNK and LKB1-Stat3-iPSC inducers in breast cancer. Furthermore, our findings can potentially open new avenues of research on the role of HNK as a novel inhibitor of stem-like phenotype.Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.Screenshot from 2024-02-23 13-55-59
https://www.sciencedirect.com/science/article/pii/S1016847823053219#s00101In the present study, we found that honokiol suppressed renal cancer cells’ metastasis via dual-blocking epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties. In addition, honokiol inhibited tumor growth in vivo. It was found that honokiol could up-regulate miR-141, which targeted ZEB2 and modulated ZEB2 expression. Honokiol reversed EMT and suppressed CSC properties partly through the miR-141/ZEB2 axis. Our study suggested that honokiol may be a suitable therapeutic strategy for RCC treatment.We found that honokiol exerted anti-tumor activities through modulating the miR-141/ZEB2 axis, and that ectopic overexpression of ZEB2 could rescue the effect of honokiol on EMT and CSC properties. It will be important to determine whether our findings are widespread in various cancer cells or cell-type-specific. In summary, our results showed that honokiol treatment significantly inhibits malignant properties of RCC cells through modulation of EMT and CSC properties; thus using honokiol may be a suitable therapeutic strategy for RCC treatmen
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842137/1 Loss of integrin-mediated signaling causes increased dependence on oncogenic H-ras in the SVR cells. FAK is activated by multiple tyrosine kinases, including VEGFR2 and PDGFRβ (27, 58). This provides a rationale for combination of tyrosine kinase inhibitors plus honokiol (18). It is well known that EGFR inhibitors are ineffective against lung cancers that have mutant ras, and the combination of honokiol and a tyrosine kinase inhibitor may result in improved efficacySubsequent reports have found that honokiol has activity against a variety of tumors. Honokiol has been found to induce apoptosis in the colon cancer cell lines RKO and to inhibit the growth of RKO cells in murine xenografts (54). We have shown that honokiol prevents the growth of MDA-MD-231 breast cancer cells in murine xenografts (59). Of interest, MDA-MD-231 cells demonstrate mutant p53 and mutant K-ras, which is preferentially observed in the triple-negative breast cancer phenotype
https://www.spandidos-publications.com/10.3892/ijmm.2019.41221Honokiol significantly suppressed cell proliferation and induced apoptosis of ovarian cancer cells by activating AMPK. Honokiol also inhibited their metastatic and invasive activities, potentially through AMPK activation. Although honokiol has been implicated in AMPK signaling in other cancer types, to the best of our knowledge, this is the first study of the role of AMPK in ovarian cancer. The results indicated that honokiol has potential clinical application for preventing and treating ovarian cancerHonokiol targets multiple signaling pathways including epidermal growth factor receptor, nuclear factor kappa-light-chain-enhancer of activated B cells B, signal transducer and activator of transcription 3, and mTOR, which serve essential roles in cancer initiation and progression (48). Previous data have suggested that honokiol affects melanoma and breast cancer cell growth by targeting AMPK signaling (28,49). However, whether AMPK targeting via honokiol is the cause its anticancer effects in ovarian cancer is unclear

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