Increased consumption of fruits and vegetables can represent an easy strategy to significantly reduce the incidence of cancer. From this observation, derived mostly from epidemiological data, the new field of chemoprevention has emerged in the primary and secondary prevention of cancer. Chemoprevention is defined as the use of natural or synthetic compounds able to stop, reverse, or delay the process of tumorigenesis in its early stages. A large number of phytochemicals are potentially capable of simultaneously inhibiting and modulating several key factors regulating cell proliferation in cancer cells. Quercetin is a flavonoid possessing potential chemopreventive properties. It is a functionally pleiotropic molecule, possessing multiple intracellular targets, affecting different cell signaling processes usually altered in cancer cells, with limited toxicity on normal cells. Simultaneously targeting multiple pathways may help to kill malignant cells and slow down the onset of drug resistance. Among the different substrates triggered by quercetin, we have reviewed the ability of the molecule to inhibit protein kinases involved in deregulated cell growth in cancer cells.

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Several malignant cell lines are resistant to CD95-(Apo1/Fas)-mediated apoptosis, even when the CD95 receptor is highly expressed. Sensitivity to CD95-induced apoptosis can be restored using different molecules. In this study, we showed that quercetin, a naturally occurring flavonoid, in association with the agonistic anti-CD95 monoclonal antibody, increases DNA fragmentation and caspase-3 activity in HPB-ALL cells. These cells have been selected for their known resistance to CD95-induced apoptosis. At molecular level, quercetin lowers the level of intracellular reactive oxygen species, reduces mitochondrial transmembrane potential, thereby leaving the expression of CD95 receptor unchanged.z 1999 Federation of European Biochemical Societies.

Haptoglobin (Hpt) binds apolipoprotein A‐I (ApoA‐I), and impairs its stimulation of lecithin:cholesterol acyltransferase (LCAT). LCAT plays a major role in reverse cholesterol transport (RCT). Apolipoprotein E (ApoE), like ApoA‐I, promotes different steps of RCT, including LCAT stimulation. ApoE contains amino acid sequences that are homologous with the ApoA‐I region bound by Hpt and are involved in the interaction with LCAT. Therefore, Hpt was expected to also bind ApoE, and inhibit the ApoE stimulatory effect on LCAT. Western blotting and ELISA experiments demonstrated that the Hpt β‐subunit binds ApoE. The affinity of Hpt for ApoE was higher than that for ApoA‐I. High ratios of Hpt with either apolipoprotein, such as those associated with the acute phase of inflammation, inhibited, in vitro, the stimulatory effect of ApoE on the cholesterol esterification activity of LCAT. Hpt also impaired human hepatoblastoma‐derived cell uptake of [3H]cholesterol from proteoliposomes containing ApoE or ApoA‐I. We suggest that the interaction between Hpt and ApoE represents a mechanism by which inflammation affects atherosclerosis progression. Hpt might influence ApoE function in processes other than RCT. Structured digital abstract  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258778: Hpt beta chain (uniprotkb:http://www.ebi.uniprot.org/entry/P00738) binds (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407) to APOE (uniprotkb:http://www.ebi.uniprot.org/entry/P02649) by filter binding (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0049)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258829, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258868: Hpt (uniprotkb:http://www.ebi.uniprot.org/entry/P00738) binds (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407) to APOA1 (uniprotkb:http://www.ebi.uniprot.org/entry/P02647) by competition binding (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0405)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258848, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258819, http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258877: APOE (uniprotkb:http://www.ebi.uniprot.org/entry/P02649) binds (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407) to Hpt (uniprotkb:http://www.ebi.uniprot.org/entry/P00738) by competition binding (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0405)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258791: Hpt (uniprotkb:http://www.ebi.uniprot.org/entry/P00738) binds (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407) to APOE (uniprotkb:http://www.ebi.uniprot.org/entry/P02649) by pull down (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0096)  http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-7258760: Hpt (uniprotkb:http://www.ebi.uniprot.org/entry/P00738) physically interacts (http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915) with APO...

We previously demonstrated that quercetin, a naturally occurring flavonoid with strong antioxidant properties, was able to enhance programmed cell death in HPB-acute lymphoblastic leukemia (ALL) cell line, derived from a human tymoma, when associated with the agonistic anti-CD95 monoclonal antibody. Here, we report that HPB-ALL cells are normally resistant to CD95-mediated apoptosis, and quercetin is able to sensitize this cell line through a mechanism independent of its antioxidant properties. In fact, other compounds structurally and functionally similar to quercetin, when associated with anti-CD95 antibody did not induce any CD95-mediated apoptosis, still maintaining their antioxidant capacity. We found that quercetin effects are mediated by the activation of PKCa. Treatment of HPB-ALL cells with quercetin slightly decreased PKCa activity, but when the flavonoid was associated with anti-CD95, the kinase activity increased by 12-fold with respect to the treatment with quercetin. In addition, overexpression of PKCa induced programmed cell death in the absence of any additional stimulus, while a kinase-defective mutant of PKCa was ineffective. Our data confirm the involvement of specific PKC isoforms in CD95 signaling and suggest, for the first time, that quercetin targets this pathway increasing apoptogenic response in a cell line resistant to CD95-mediated apoptosis.

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