stilbenes and Salivary-Gland-Neoplasms

The survival rate of head and neck squamous cell carcinomas (HNSCC) patients has not considerably changed over the last two decades. Polyphenols inhibit the growth of cancer cells. We determined whether the combination of Resveratrol (RES) and Curcumin (CUR) enhanced their in vitro and in vivo antitumor activities on HNSCC cell lines compared to the single compounds. We provide evidence that RES potentiated the apoptotic effect and reduced the IC50 of CUR on HNSCC cell lines. The model of compounds interaction indicated the onset of an additive effect of the two compounds compared to the single treatment after decrease of their concentrations. RES+CUR compared to CUR increased the PARP-1 cleavage, the Bax/Bcl-2 ratio, the inhibition of ERK1 and ERK2 phosphorylation, and the expression of LC3 II simultaneously with the formation of autophagic vacuoles. RES and CUR induced cytoplasmic NF-κB accumulation. RES+CUR administrations were safe in BALB/c mice and reduced the growth of transplanted salivary gland cancer cells (SALTO) more efficiently than CUR. Overall, combinations of CUR and RES was more effective in inhibiting in vivo and in vitro cancer growth than the treatment with CUR. Additional studies will be needed to define the therapeutic potential of these compounds in combination.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Proliferation; Curcumin; Drug Synergism; Fluorescent Antibody Technique; Head and Neck Neoplasms; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Phosphorylation; Reactive Oxygen Species; Resveratrol; Salivary Gland Neoplasms; Signal Transduction; Stilbenes; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Resveratrol, a well-established phytoestrogen and chemopreventive agent, has gained much attention among oncologists because it can act as both estrogen receptor agonist and antagonist, depending on dosage and cell context. It is increasingly accepted that steroidal receptor coregulators may also function in the cytoplasmic compartment. Deregulation and altered localization of these coregulators could influence target gene expression and participate in the development of hormone-responsive cancers. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1), a novel estrogen receptor (ER) coactivator, plays an important role in the genomic and nongenomic actions of ER. Furthermore, recent studies have shown that differential compartmentalization of PELP1 could be crucial in modulating sensitivity to tamoxifen. In this study, we investigated the role of PELP1 in resveratrol-induced autophagy in lung cancer and salivary gland adenocarcinoma cell lines. Resveratrol reversibly inhibited the growth of these cancer cell lines and induced autophagy, as evidenced by microtubule-associated protein 1 light chain 3 (LC3) up-regulation in a time-dependent and 3-methyladenine-sensitive manner. Confocal microscopic analysis showed that resveratrol induced PELP1 accumulation in autophagosomes with green fluorescent protein-LC3. The intermediary molecule involved in PELP1 accumulation in resveratrol-induced autophagosomes is hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a trafficking molecule that binds to PELP1. These results identify PELP1 for the first time in autophagosomes, implying that both PELP1 and HRS reallocate to autophagosomes in response to resveratrol treatment, which might be important in the process of autophagy in the cancer cells.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Autophagy; Cell Cycle; Cell Proliferation; Co-Repressor Proteins; Endosomal Sorting Complexes Required for Transport; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Lysosomes; Microtubule-Associated Proteins; Models, Biological; Phosphoproteins; Protein Transport; Receptors, Estrogen; Resveratrol; Salivary Gland Neoplasms; Stilbenes; Trans-Activators; Transcription Factors; Tumor Cells, Cultured

Cancer results from an undesirable imbalance between cellular proliferation and apoptosis. Both processes may be modulated at the level of gene expression, viz., p53 and c-Ha-ras, by dietary bioactive components such as resveratrol. We tested the time-dependent effect of resveratrol on gene and protein expression in WR-21 cells containing a mutated human c-Ha-ras oncogene. We demonstrate cyclic resveratrol-mediated expression of p53, mdm2, p21(cip/waf), Rb, and cyclin G at both the RNA and the protein level at <8 h. However, ras was not differentially expressed at either the RNA or the protein level. p53 was upregulated followed by p21cip/waf, then mdm2, and cyclin G, all downstream p53-activated targets. RNA transcription increased at >8 h for all genes except p53, but protein levels did not suggest uncoupling of transcription and translation. At 24 h, both p53 and Rb expression returned to baseline, suggesting collapse of DNA structure and spindle assembly checkpoints characteristic of mitotic catastrophe. In summary, resveratrol at <8 h induced p53-mediated effects, including apoptosis and cell-cycle arrest (G2/M). However, later, it induced cell-cycle checkpoint dysfunction, indicative of mitotic catastrophe. Thus, future studies should better elucidate the temporal mechanism of the dietary bioactive agent resveratrol on cancer cells.

Topics: Animals; Anticarcinogenic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cyclin G; Cyclin G1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Gene Expression; Genes, p53; Genes, ras; Humans; Mice; Mutation; Proto-Oncogene Proteins c-mdm2; Resveratrol; Retinoblastoma Protein; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salivary Gland Neoplasms; Stilbenes; Time Factors; Tumor Suppressor Protein p53