Honokiol, a multifunctional antiangiogenic and antitumor agent

Abstract

Honokiol is a small-molecule polyphenol isolated from the genus Magnolia. It is accompanied by other related polyphenols, including magnolol, with which it shares certain biologic properties. Recently, honokiol has been found to have antiangiogenic, antiinflammatory, and antitumor properties in preclinical models, without appreciable toxicity. These findings have increased interest in bringing honokiol to the clinic as a novel chemotherapeutic agent. In addition, mechanistic studies have tried to find the mechanism(s) of action of honokiol, for two major reasons. First, knowledge of the mechanisms of action may assist development of novel synthetic analogues. Second, mechanistic actions of honokiol may lead to rational combinations with conventional chemotherapy or radiation for enhanced response to systemic cancers. In this review, we describe the findings that honokiol has two major mechanisms of action. First, it blocks signaling in tumors with defective p53 function and activated ras by directly blocking the activation of phospholipase D by activated ras. Second, honokiol induces cyclophilin D, thus potentiating the mitochondrial permeability transition pore, and causing death in cells with wild-type p53. Knowledge of the dual activities of honokiol can assist with the development of honokiol derivatives and the design of clinical trials that will maximize the potential benefit of honokiol in the patient setting.

FIG. 1.

Metabolic pathway of honokiol in cells that use a ras signaling schema. Honokiol acts on the ras-Rhoa complex to inhibit PLD expression. The inhibition of PLD expression then causes consequential apoptosis in cells. Honokiol can also act on cyclophilin D, via a loss of the p16ink4a pathway, which can induce necrosis or autophagy via two distinct pathways. The first is the cyclophilin D effect to upregulate Jnk1, causing bcl2 to phosphorylate, causing autophagy. The second is the effect on WT p53 and bcl2, which leads to mitochondrial permeability via the transition pore. The second route leads the breakdown of the cellular system and necrosis.

FIG. 2.

A possible chemical mechanism in which honokiol acts as a reactive oxygen (ROS) scavenger. This allows honokiol to act as a significant inhibitor in reactive oxygen species (ROS)-driven tumors. This inhibition is in part a result of the effect that honokiol has on the expression of phospholipase D (PLD) in the ras pathway. The direct effect of honokiol is on the Ras-RhoA-ral complex, which leads to the expression of phospholipase D (PLD). The expression of PLD from this complex is induced by rac, which is involved with PI3K and a receptor activated by growth factors. Ultimately, PLD activated IKK and IκB activity, which leads to tumor growth. The Ras-RhoA-ral is induced by serum deprivation. Studies have been done with the combination of both serum-deficient tumors with treatment of honokiol, varying from 10 to 15% deficient. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

A table of analogues, including honokiol and magnolol. This table includes data on compound activity against angiosarcoma (SVR cells) in varying concentrations and its activity against HIV, which demonstrate its antiviral properties. Alongside this information in columns 6, 7, and 8, the data show the cytotoxicity of honokiol and its analogues in three normal human cell lines. With this information, one can gather the benefits of honokiol and its analogues in antitumor and antiviral schemas, with minimal cytotoxic effects (4).

FIG. 4.

Postulated products of peroxide scavenging by honokiol. Such compounds can include endoperoxides, bridged endoperoxides, or nitrophenols. As shown, multiple combinations of oxygenated honokiol can exist with ring enclosures common in scavenging compounds.

FIG. 5.

Honokiol enhances the complexing of the α₂ subunit to the GABA_A receptor, which allows better binding of (3)H-muscimol to the GABA_A receptor. This enhanced binding allows better activation of the neuron and more sustained signal. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 6.

Purification of honokiol from Magnolia. Protection of magnolol with dimethoxypropane to make the magnolol-acetonide enables honokiol to be purified via chromatography. Without the protection, both magnolol and honokiol, which are structural isomers of each other, have the same polarity and cannot be separated. The protected magnolol can be deprotected by using acid.

FIG. 7.

The Muara-Suzuki coupling mechanism. This synthetic process is the palladium-catalyzed cross-coupling between two phenolic rings into a bisphenol compound. The mechanism of the Suzuki reaction is best viewed from the perspective of the palladium catalyst. The first step is the oxidative addition of palladium to the halide to form the organo-palladium species. Reaction with base gives the intermediate, which, via transmetalation with the boronate complex, forms the organopalladium species. Reductive elimination of the desired product restores the original palladium catalyst.

FIG. 8.

Synthetic scheme of honokiol and its derivatives. The synthesis of honokiol derivatives by using various bisphenol starting materials via an allylation of the phenolic hydroxyl groups and then the Claisen rearrangement. Various derivatives have different effects on targets and varying toxicity.