Honokiol shows promise in preclinical and early clinical studies for its anti-cancer mechanisms.

The structural diversity and easy binding ability of natural compounds make them unique in participating in the physiological process of life. Nature is an essential resource for discovering anti-cancer drugs or lead compounds, with 80-83% of small-molecule anti-cancer drugs available today being derived from natural products or their modified derivatives.

Research on the mechanisms of the Honokiol the compound extracted from Magnolia bark is still ongoing. Honokiol has been found to work in many powerful ways.

The Effects of Honokiol on Cancer Cell Metabolism

Honokiol inhibits cancer cell growth by reducing energy production through glycolysis. These effects are dependent on HIF1α. In HIF1α driven glycolysis, Honokiol can decrease glucose uptake and lactic acid production while increasing oxygen consumption. Radiation therapy and chemotherapeutic agents like doxorubicin and cisplatin can activate HIF1α, which leads to increased HIF1α driven glycolysis in cancer cells and resistance to treatment under hypoxic conditions. Even targeted therapies like TKIs can induce HIF1α driven glycolytic metabolism in tumours.

When viewed through the lens of anti-fungal research, Honokiol triggers signalling pathways that generally respond to oxidative stress, modulated glucose transporters and glycolysis metabolic enzymes, resulting in a decrease in ATP production and activation of cell death pathways.

Honokiol Targets Cancer Angiogenesis

Tumours rely on angiogenesis, as the blood supplies the nutrients and growth the tumour requires. Honokiol has been shown to possess anti-angiogenic properties, which may help to slow down the growth and spread of tumours. The development of blood vessels relies on endothelial cells, which Honokiol has been found to inhibit. Honokiol can suppress pro-angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). All these factors promote angiogenesis and encourage the growth of blood vessels, but Honokiol can down-regulate their expression. Honokiol also inhibits interleukin-induced angiogenesis in the tumour microenvironment through the NF-κB signalling pathway.

Honokiol disrupts pathways involved in angiogenesis.

Honokiol Studies have demonstrated that Honokiol can decrease the levels of MMPs, including MMP-2, MMP-9, and MMP-14. As many know, these MMPs are often linked to cancer progression and metastasis. Honokiol can limit the production of these enzymes, which can reduce their ability to break down the extracellular matrix (ECM) and enable tumour invasion.  TIMP-1 and TIMP-2 are increased, and the activity of the MMPs is significantly reduced, suppressing tumour growth

Not only that but, Honokiol can also directly target the already active sites of MMPs to prevent them from breaking down important ECM components such as collagen and fibronectin. By reducing MMP activity, Honokiol can help preserve the ECM's integrity, which is crucial in preventing tumour invasion and metastasis.

 It is important to note that regulating MMP activity is crucial in the fight against cancer, and using a highly bioavailable, pure, high-strength Honokiol may be highly beneficial in achieving this goal. Honokiol's effects on MMPs vary depending on cancer type, microenvironment, and experimental conditions.

Honokiol induced both autophagy and apoptosis via the PI3K/Akt/mTOR signalling pathway

Unlike other PI3K/mTOR inhibitors, Honokiol can reduce this pathway's activity in tumour cells while leaving critical pro-inflammatory T cell functions unaffected. Specific inhibitors like LY294002, Wortmannin, AKT inhibitor III, and Rapamycin do not have this selective effect.

In cancer, the PI3K/AKT/mTOR pathway can become disrupted, leading to an increase in signals for cell growth and survival. This pathway plays a vital role in regulating cell growth, metabolism, and survival and is crucial for several cellular processes, such as differentiation, proliferation, and survival. The PI3K/AKT/mTOR pathway is of utmost importance in ongoing cancer research, as it is intricately linked to comprehending the mechanisms of treatment resistance in chemotherapies, targeted therapies, and immunotherapies.

Many cancer cell types are responding well to Honokiol

Honokiol has demonstrated good anti-cancer activity against various cancer cells, including breast, lung, bone, colon, bladder, brain, and blood cancer cells. Recent research suggests that Honokiol may effectively overcome immunotherapy resistance in certain types of cancer, such as glioma, breast, and prostate cancer. Dig further here

Research has also shown that Honokiol has an inhibitory effect on NF-κB activity in various types of cancer, including breast cancer, cholangiocarcinoma, colon cancer, liver cancer, lung cancer, myeloma, ovarian cancer, and skin cancer. In an osteosarcoma cell model, Honokiol can both prevent the growth of tumours and increase their rate of apoptosis.

Honokiol caused an increase in the expression of Bcl-2-like protein 4, caspase-3 and p53 protein expression while suppressing the expression of cyclin D1 protein in osteosarcoma cells.

Honokiol and Breast Cancer alone and in combination with oncology drugs. It has been proven to inhibit growth in both estrogen receptor-positive and -negative cell lines, including drug-resistant breast cancer cells. This inhibition is associated with the arrest of cell cycle and the induction of apoptosis. Once again, Honokiol also attenuates the PI3K/Akt/mTOR signalling pathway and shows synergistic effects when combined with the mTOR inhibitor rapamycin.

Honokiol can potentially inhibit the cell cycle of metastatic breast cancer stem cells. This research article on Honokiol in 2022 focused on breast cancer stem cells and their role in chemoresistance, metastasis, and poor prognosis of breast cancer. The authors investigate the potential of Honokiol to target BCSCs and modulate the tumour microenvironment for improved immunotherapy. Using bioinformatics analyses, they predict Honokiol protein targets, and in concert with leading breast cancer projects worldwide pinpoint genes differentially expressed in metastatic breast cancer stem cells. The therapeutic targets of Honokiol include the most common metastatic breast cancer genes CCND1, SIRT2, AURKB, VEGFA, HDAC1, CASP9, HSP90AA1, and HSP90AB1. Honokiol has the potential to inhibit the cell cycle of metastatic breast cancer stem cells. The same paper also highlights Honokiol's impact on various signalling pathways and its potential as an immunotherapeutic agent for mBCSCs.

Overall, Honokiol is a promising treatment for breast cancer.

A study on NSCLC cells discovered that Honokiol will bring about G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Cancer can use autophagy to escape cell death, so by simultaneously blocking autophagy with an autophagic inhibitor; they increase the compound’s anti-cancer activity both in vitro and in vivo. This work implies that autophagy was protective in Honokiol-induced cancer cell death. The study suggests that a bioavailable Honokiol combined with an autophagic inhibitor could be a viable option for further investigation into NSCLC treatment. A clinical trial is underway in China.