196,059 research outputs found
Potential role of the natural multi-targeted agent curcumin in the treatment of oral diseases.
No full textWe critically review the current data on the therapeutic effects and basic biological activities of the natural compound curcumin on various oral diseases: a sound experimental evidence appears to support its possible use against relevant pathologies which include cancer, radiotherapy- and chemotherapy-induced mucositis, lichen planus and periodontitis. This versatility of curcumin depends on its ability of interacting with multiple targets, though inhibition of the transcription factor NF-kB can be identified as one of the principal mechanisms. The therapeutic potentialities of curcumin in oral medicine have, however, to be further verified, in particular by more human ad hoc in vivo studies. An important aspect that remains to resolve is that of improving by adequate approaches the topical or systemic delivery of the drug to the target tissues. At present there is also a very active search for the synthesis of new curcumin derivatives endowed with improved pharmacokinetic and pharmacodynamic characteristics
Meccanismi antitumorali degli oli essenziali estratti da piante succulente in un modello di leucemia mielocitica acuta multifarmacoresistente
No full textEssential oil of Cyphostemma juttae (Vitaceae): chemical composition and antitumor mechanism in triple negative breast cancer cells
No full textThe genus Cyphostemma (Planch.) Alston (Vitaceae) includes about 150 species distrib- uted in eastern and southern Africa and Madagascar. Some species are used in traditional medicine and their biological activities, including antiproliferative effects against cancer cell lines, have been demonstrated. To date no investigations on Cyphostemma essential oils have been carried out. Essential oils, which play important roles in plant defenses have been demonstrated to be active in the treatment of several human diseases and to enhance bioavability of other drugs. The aim of this paper was to identify the chemical composition of the essential oil of the leaves of Cyphostemma juttae (Dinter & Gilg) Desc. and to verify some biological activities on two triple negative breast cancer cell lines (MDA-MB-231, SUM 149), characterized by the over-expression of the transcription factor NF-κB. In the essential oil, obtained by hydrodistillation and analysed by gas chromatography-mass spectrometry, 39 compounds were detected and with phytol (30%) dominating the chemical composition. C. juttae essential oil reduced cell growth and showed a pro-oxidant activity in both cell lines. Moreover, C. juttae essential oil caused a substantial decrease of NF-κB activation and consequently a significant reduction of some NF-κB target genes. The present study shows for the first time the cytotoxic properties of C. juttae essential oil and highlight its avail- ability to interfere with NF-κB pathway, suggesting a potential therapeutic use in triple nega- tive breast cancers (TNBCs) of this essential oil
NF-kB Is a Potential Molecular Drug Target in Triple-Negative Breast Cancers
No full textBreast cancer continues to cause significant burden in global health morbidity and mortality. Triple-negative breast cancers (TNBCs) are highly aggressive with poor prognosis and are characterized by lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (Her-2). TNBCs are often resistant to cytotoxic chemotherapy and pose major difficulty in achieving personalized medicine due to their molecular heterogeneity. There is increasing evidence that the aberrant activation of nuclear factor (NF)-kB signaling is a frequent characteristic of TNBCs. We evaluated the effects of different potential NF-kB inhibitors, such as bisindolylmaleimide I (BIS, a selective protein kinase C [PKC] inhibitor),MG132 (a proteasome inhibitor), curcumin (endowed with pleiotropic activities), and dehydroxymethylepoxyquinomicin (an inhibitor of NF-kB translocation into the nucleus) on the constitutive activation of NF-kB present in three TNBC cell lines (SUM149, SUM159, and MDA-MB-231). Wealso evaluated whether MDA-9/Syntenin plays a role in NF-kB activation, as observed in other cancer types. Indeed, silencing experiments with a siRNA anti-MDA-9/Syntenin produced a very strong reduction of NF-kB activation in all the three TNBC cell lines. We conclude that different approaches targeting NF-kB activation might potentially prove useful for innovation in anticancer drug development for TNBCs. Further research that bridge preclinical and clinical investigations with NF-kB inhibitors would be timely and warranted
Expression of a specific Thymidylate synthase polimorfic allele in metastatic colorectal patients is regulated by Myeloid Zinc Finger 1.
No full textThymidylate Synthase (TS) is the target enzyme for fluoropyrimidine anticancer drugs. Its expression is regulated by the number of functional upstream stimulatory factor (USF) E box consensus elements present on its 5’ untranslated region. To date are known different polymorphisms, the first one consisting of 2 or 3 repeat of a 28 bp sequence, a further single nucleotide polymorphism (SNP) consisting in a G>C substitution within the second repeat of 3R (3RG>3RC) and recently it has been identified an additional SNP a G>C substitution at the 12th nucleotide in the first repeat of the 2R allele (2RG>2RC). These polymorphisms can influence TS expression, in particular 3R/3R genotype and the presence of 3RG alleles are associated to an increased transcriptional activity and to higher TS levels. The sequence of promoter region of colorectal cancer (CRC) samples was subjected to an in silico analysis (http://www.cbrc.jp/research/db/TFSEARCH.html) to search for all potential transcription factors binding this region. We found that Myeloid zinc finger 1(MZF-1) binds the analyzed consensus. By the literature it is known that this factor induces invasion and in vivo metastasis in CRC, so we investigated a possible correlation between TS and MZF-1 expression in the same pathological samples. Materials and Methods: we analyzed the distribution of these polimorphisms in a group of 68 healthy Caucasian subjects, in the normal tissue, in primary tumour and in liver metastasis of 13 CRC patients. Tandem repeat length and the presence of SNP was determined by direct sequencing of genomic DNA. TS and MZF 1 expression were analyzed by immunohistochemistry. Results: In healthy population the allele frequency was respectively 2RG(35%) 3RG (44%) 3RC (21%), in colorectal patients while both primary that normal and metastatic samples showed the same genotype: 2RG/3RG. TS and MZF-1 expression were related and gradually increased from normal tissue (negative) to the primary tumour (focally positive) in the metastases (overexpressing). Conclusions: These unexpected results lead to the hypothesis of a genetic selection towards a more aggressive disease and enough suggest that regardless of genotype other factors are involved in regulation of TS expression as MZF 1, therefore the only genetic marker is not a valid predictor of eventual fluoropyrimidine response
Antitumor effects of curcumin in human hepatic cancer cells: Analysis of their relationship to inhibition of NF-kB and pro-survival gene expression.
No full textAntitumor effects of curcumin, alone or in combination with cisplatin, on hepatic cancer cells. Analysis of their relationship to IL-6 production
No full textThe antitumor activities of curcumin and of its novel isoxazole analogue MR 39 are not hampered by the multidrug resistant condition of tumor cells expressing both P-glycoprotein and different inhibitory of apoptosis proteins
No full textSignificance of Autologous Interleukin-6 Production in the HA22T/VGH Cell Model of Hepatocellular Carcinoma
No full textCancer cells may often support their own growth, survival,
and drug resistance by autocrine/paracrine loops based on the production of different factors; results from us and others have shown that similar interleukin-6 (IL-6)-related loops are operative in multiple myeloma
and prostate or renal cancer. Because this aspect has not been investigated in detail for hepatocellular carcinoma (HCC), we have examined it in HA22T/VGH cells. These differ from other primary liver
cancer cell lines (that is, HepG2, HuH-6, and HuH-7) in that enzymelinked immunosorbent assay (ELISA) showed the HA22T/VGH cells to
secrete remarkable amounts of IL-6 (16.8 ng /106 cells/24 h); this production, due to constitutive activation of NF-B, is inhibited by agents
like curcumin and dehydroxymethylepoxyquinomicin (DHMEQ), which
interfere with the transcription factor. Flow cytometry, ELISA, mRNA,
and Western blotting analyses were performed to characterize the status of the IL-6 receptor in HA22T/VGH cells. Two transmembrane
glycoproteins that form the functional IL-6 receptor have been
identified: the ligand-binding gp80 and the signal-transducer gp130. Soluble forms of gp80 also trigger membrane gp130 signaling when complexed with IL-6, while soluble forms of gp130 inhibit the same process. Our results showed that HA22T/VGH cells express gp130 at their
surface, but release only traces of its soluble form. For gp80, the cells
produced the mRNAs of both its membrane and soluble form. However, in immunoblotting they exhibited a very faint content of the same
subunit, which, in addition, was neither expressed at the cell surface
nor secreted. In MTT assays, incubation with a neutralizing anti-IL-6 antibody for up to 7 days did not affect the growth of HA22T/VGH cells.
Also, other specific anti-IL-6 approaches (siRNA or AODN) failed to produce this result. In conclusion, autostimulatory loops mediated by IL-6
are less likely to occur in HCC than in other kinds of cancer. However,
since release of IL-6 is frequent in HCC, especially in its more advanced
stages, the use of agents like curcumin or DHMEQ might be beneficial
to counteract its adverse systemic effects (e.g., cachexia)
Synthesis of Curcumin Derivatives and Analysis of Their Antitumor Effects in Triple Negative Breast Cancer (TNBC) Cell Lines
No full textWe analyzed antitumor effects of a series of curcumin analogues. Some of them were obtained by reaction of substitution involving the two phenolic OH groups of curcumin while the analogues with a substituent at C-4 was prepared following an original procedure that regards the condensation of benzenesulfenic acid onto the nucleophilic central carbon of the curcumin skeleton. We analyzed cytotoxic effects of such derivatives on two TNBC (triple negative breast cancer) cell lines, SUM 149 and MDA-MB-231, but only three of them showed an IC50 in a lower micromolar range with respect to curcumin. We also focused on these three derivatives that in both cell lines exhibited a higher or at least equivalent pro-apoptotic effect than curcumin. The analysis of molecular mechanisms of action of the curcumin derivatives under study has highlighted that they decreased NF-κB transcriptional factor activity, and consequently the expression of some NF-κB targets. Our data confirmed once again that curcumin may represent a very good lead compound to design analogues with higher antitumor capacities and able to overcome drug resistance with respect to conventional ones, even in tumors difficult to treat as TNBC
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