Honokiol: a novel natural agent for cancer prevention and therapy

Abstract

Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,4'-diol) is a bioactive natural product derived from Magnolia spp. Recent studies have demonstrated anti-inflammatory, anti-angiogenic, anti-oxidative and anticancer properties of honokiol in vitro and in preclinical models. Honokiol targets multiple signaling pathways including nuclear factor kappa B (NF-κB), signal transducers and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (m-TOR), which have great relevance during cancer initiation and progression. Furthermore, pharmacokinetic profile of honokiol has revealed a desirable spectrum of bioavailability after intravenous administration in animal models, thus making it a suitable agent for clinical trials. In this review, we discuss recent data describing the molecular targets of honokiol and its anti-cancer activities against various malignancies in pre-clinical models. Evaluation of honokiol in clinical trials will be the next step towards its possible human applications.

Figure 1

Honokiol and its derivatives. Three novel anti-tumor derivatives of honokiol namely 3’- formylhonokiol, 5-formylhonokiol and 3’, 5-diformylhonokiol are prepared after treating the honokiol with chloroform in 35% sodium hydroxide solution in presence of tetrabutyl ammonium bromide as phase transfer catalyst under 50 °C for 3 h. Out of these derivatives 3’- formylhonokiol and 5-formylhonokiol are isomers. Among honokiol and its three C-formylation derivatives, 5-formylhonokiol displayed the strongest inhibitory ability on tumor cell lines.

Figure 2

A schematic diagram depicts the mechanism of action of honokiol through various molecular targets that results in chemopreventive and chemotherapeutic activity. Honokiol inhibits nuclear factor-κB (NF-κB), signal transducers and activator of transcription (STAT-3), epidermal growth factor receptor (EGFR), mammalian target of rapamycin (m-TOR) or Mitogen-activated protein kinases (MAPK) followed by downstream inhibition of cytokines, inducible enzymes, adhesion molecules, cell cycle and apoptosis-related molecules involved in inflammation, proliferation, angiogenesis, invasion and metastasis.

Figure 3

Schematic representation of pharmacokinetic profile of honokiol. Honokiol has poor GIT absorption, bio-transformed in liver to mono-glucuronide honokiol and sulphated mono-hydroxyhonokiol, ~ 50% is secreted in bile, ~ 60-65% plasma protein bound and ~ 27% is excreted in the urine with elimination half life of (t1/2) of 49.05 – 56.24 minutes.