Chemoprevention of Hepatocarcinogenesis with Dietary Isoprenic Derivatives: Cellular and Molecular Aspects

Abstract

Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and β- ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach.

Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases

“…Using mice with intracranially-implanted, drug-resistant human glioblastoma cells, Cho et al [ 107 ] administered POH into the nostrils of animals once every other day. The highest dosage applied was only 1.9 mg/kg, which is substantially lower than what was commonly used in earlier in vivo experiments with oral gavage or intraperitoneal injections of POH [ 93 , 94 , 95 ]. The results showed extended survival of POH-treated animals, clearly demonstrating the therapeutic efficacy of intranasal POH.…”

“…POH is a natural monocyclic terpene derived from limonene and the mevalonate pathway in certain plants, such as citrus, peppermint, spearmint, lavender and lilac oils, sage, celery, cherries and others [ 92 ]. When administered orally to different types of xenograft mouse or rat tumor models, it revealed potent activity against different types of cancer, including those of the breast, liver and pancreas [ 93 , 94 , 95 , 96 , 97 ]. In the chicken chorioallantoic membrane (CAM) model, POH blocked the migration of C6 rat glioma cells [ 98 ].…”

Le limonène dans les huiles essentielles : énantiomères et activités biologiques

“…Il a des effets anti-inflammatoires dans les modèles de l'arthrose [86] et de l'asthme [87,88]. Le limonène est métabolisé en alcool périllique ou hydroxy-7 paramenthadiène 1-8 (C 10 H 16 O), qui fait également l'objet de nombreuses études sur le cancer [89].…”

Antisense oligonucleotides directed against insulin-like growth factor-II messenger ribonucleic acids delay the progress of rat hepatocarcinogenesis

“…[12] HCC is characterized by multiple causes, multiple stages and multifocal process of tumorigenesis related intimately to the overexpression/suppression of many cellular factors. [34] In general, chemical-induced liver cancer (hepatocarcinogenesis) animal models have been widely used for investigating therapeutic and other combating strategies in vivo against HCC. Transformation of hepatocytes to HCC occurs through multiple genetic alterations and protein expressions.…”