Published:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2014
Language:
English
Identifier:
Origination:
University thesis:
Dissertation, 2014
Footnote:
Description:
Chemoprevention is an approach based on the use of natural or synthetic compounds to inhibit, suppress or reverse the development and progression of cancer. In order to overcome the cancer disease, the identification of chemopreventive compounds is of particular interest. Among them, antimutagens prevent the mutagen-induced DNA-injury or promote the repair and/or the reversion of damage. In addition to antimutagenicity, some agents also act as chemosensitizers, by increasing the effectiveness of cancer chemotherapy and radiotherapy, when used in combination with chemotherapeutical agents. This approach is very interesting to prevent the development of multidrug resistance (MDR), which makes cancer cells not-sensitive to a broad range of drugs. In this context, present study was aimed at evaluating the potential chemopreventive properties of some natural and naturally-derived compounds, particularly the sesquiterpenes β-caryophyllene (CRY) and β-caryophyllene oxide (CRYO), and the aldehyde α-hexylcinnamal (HCA). The antimutagenic activity was evaluated by the reverse bacterial mutation assay (Ames test), on different strains of Salmonella typhimurium and Escherichia coli, both in absence and presence of the S9-metabolic activation system. As mutagens, 2- nitrofluorene (2NF), sodium azide (SA), methyl methanesulfonate (MMS), 2-aminoanthracene (2AA), benzo[a]pyrene (BaP), 4-nitroquinoline N-oxide (4NQO), 1-nitropyrene (1NP), 1,8-dinitropyrene (1,8-DNP) and a sample of condensed smoke (CSC) from standard 3R4F cigarette were used. In addition to antimutagenicity studies, the potential chemosensitizing properties of CRY, CRYO and HCA and their ability to interfere with ABC-transporter function were evaluated, in Caco-2, CEM/ADR5000 and CCRF/CEM human cancer cells. For each compound, low concentrations (IC10 and IC20) were assayed in order to verify their potential additive, synergistic or antagonistic effects with the anticancer doxorubicin. The nature and the extent of the interaction were evaluated by the combination index (CI) and the isobologram analysis, respectively; conversely, the potential enhancement of drug effectiveness was quantified by cytotoxicity enhancement ratio (RR). The interaction between test compounds and ABC-transporters was studied by the rhodamine 123 assay. HCA exhibited an antimutagenic activity against different nitro-compounds and in various experimental protocols, suggesting the involvement of both desmutagenic and bioantimutagenic mechanisms. The sesquiterpenes CRY and CRYO resulted able to inhibit the mutagenicity of CSC, although with different potency and specificity: CRYO was the most potent compound, acting at concentrations about ten-times lower than CRY. The antimutagenicity was highlighted in different strains and in all experimental protocols, suggesting the overlapping of various protective mechanisms; the inhibition of CSC-induced oxidative stress seems to be likely and deserves further investigations. In human cancer cells, the substances produced cytotoxic effects at high concentrations both in resistant and in sensitive cell lines: HCA was the most effective substance, especially in the sensitive CCRF-CEM cells. All the compounds synergistically acted with doxorubicin, although HCA was the most potent: IC20 HCA increased the doxorubicin cytotoxicity of about six, seven and fourthy-seven folds, in Caco-2, CEM/ADR5000, and CCRF-CEM, respectively. In addition, a remarkable inhibition of ABCtrasporter was produced by HCA in the cancer cells tested: the effect was higher than that of the standard inhibitior verapamil. Also CRY and CRYO inhibited the ABC transporters but with lower potency than verapamil. The antimutagenic and chemosensitizing properties of β-caryophyllene, β-caryophyllene oxide and the α-hexylcinnamaldehyde deserves attention and represent a starting point to better evaluate their potential applications in the field of chemoprevention.