RESUMO
Humans typically consume "natural agents" that are believed to be chemoprotective and are known to decrease inflammation biomarker NF-kappaB in vitro; however, no intervention studies in humans have been done to date. This commentary documents the in vivo results as a powerful example for supporting the superiority of a complex mixture of natural agents. Human volunteers consumed two 500 mg capsules (BID) containing a mixture of natural agents for a period of 2 weeks, and blood samples were collected pre- and post-intervention. The purified lymphocytes were subjected to ex-vivo exposure to TNF-alpha or kept as untreated control. The mean NF-kappaB DNA binding activity was increased upon TNF-alpha treatment in pre-intervention samples; however, TNF-alpha was unable to induce NF-kappaB in post-intervention samples, suggesting that the mixture of four important natural agents could be useful to protect humans against oxidative stress.
Assuntos
Produtos Biológicos/uso terapêutico , Linfócitos/efeitos dos fármacos , NF-kappa B/imunologia , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Adulto , Produtos Biológicos/farmacologia , Catequina/análogos & derivados , Catequina/uso terapêutico , Curcumina/uso terapêutico , DNA/metabolismo , Feminino , Humanos , Isoflavonas/uso terapêutico , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neoplasias/prevenção & controle , Adulto JovemRESUMO
Curcumin induces cancer cell growth arrest and apoptosis in vitro, but its poor bioavailability in vivo limits its antitumor efficacy. We have previously evaluated the bioavailability of novel analogues of curcumin compared with curcumin, and we found that the analogue CDF exhibited greater systemic and pancreatic tissue bioavailability. In this study, we evaluated the effects of CDF or curcumin alone or in combination with gemcitabine on cell viability and apoptosis in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer (PC) cell lines. Mechanistic investigations revealed a significant reduction in cell viability in CDF-treated cells compared with curcumin-treated cells, which were also associated with the induction of apoptosis, and these results were consistent with the downregulation of Akt, cyclooxygenase-2, prostaglandin E(2), vascular endothelial growth factor, and NF-kappaB DNA binding activity. We have also documented attenuated expression of miR-200 and increased expression of miR-21 (a signature of tumor aggressiveness) in gemcitabine-resistant cells relative to gemcitabine-sensitive cells. Interestingly, CDF treatment upregulated miR-200 expression and downregulated the expression of miR-21, and the downregulation of miR-21 resulted in the induction of PTEN. These results prompt further interest in CDF as a drug modality to improve treatment outcome of patients diagnosed with PC as a result of its greater bioavailability in pancreatic tissue.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Curcumina/farmacologia , Desoxicitidina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/biossíntese , Neoplasias Pancreáticas/tratamento farmacológico , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Curcumina/administração & dosagem , DNA Complementar/genética , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Sinergismo Farmacológico , Inativação Gênica , Humanos , MicroRNAs/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Oligonucleotídeos Antissenso/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transfecção , Triterpenos/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , GencitabinaRESUMO
PURPOSE: Emerging evidence clearly suggests the potential chemopreventive and anti-tumor activity of a well known "natural agent" curcumin. However, studies have shown that curcumin is not readily bioavailable, and thus the tissue bioavailability of curcumin is also poor except for gastrointestinal track. Because of the potential biological activity of curcumin, many studies have attempted for making a better analog of curcumin that is equally effective or better with increased bioavailability, which was the purpose of our current study. METHODS: We have designed and synthesized new difluoro Knoevenagel condensates of curcumin and Schiff bases along with their copper (II) complexes and evaluated their biological activities with respect to the inhibitory effects on purified rabbit 26S proteasome, and growth inhibition and induction of apoptosis in colon and pancreatic cancer cell lines. RESULTS: All copper complexes possess distorted square planar geometries with 1:1 metal to ligand stoichiometry with reversible copper redox couple. The difluoro compound CDF exhibited inhibitory effects on purified rabbit 20S proteasome or cellular 26S proteasome, and caused both growth inhibition of cancer cell lines and induced apoptotic cell death in our preliminary assessment. CONCLUSION: Our results suggest that our newly synthesized classes of curcumin analogs could be useful as chemopreventive and/or therapeutic agents against cancers.
