phenanthrenes and Thyroid-Neoplasms

Thyroid cancer is a familiar kind of cancer. Natural products are promising therapeutic approaches in treating thyroid cancer. Triptolide is a diterpenoid epoxide extracted from. We evaluated triptolide targets and thyroid cancer targets with related databases. The protein-protein interaction (PPI) networks of the triptolide targets and thyroid cancer targets were constructed with Cytoscape software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the core PPI network were obtained. Molecular docking analysis was used to evaluated the binding of triptolide with core targets. Furthermore, apoptosis assays, real-time polymerase chain reaction (RT-PCR) and Western blotting were used to evaluate the anticancer functions of triptolide.. Triptolide had 34 targets, and thyroid cancer had 210 targets. The core PPI network of merged PPI networks had 164 nodes and 4513 edges. GO and KEGG enrichment analyses showed that triptolide were related to the cell cycle, apoptosis, and inflammatory signaling pathways. Molecular docking analysis showed that triptolide directly reacted with four core targets: cyclin-dependent kinase inhibitor 1A (CDKN1A), c-JUN, RELA, and tumor protein p53 (TP53). CB-Dock analysis indicated that triptolide could stably bind to core targets. Triptolide inhibited the growth but induced apoptosis of thyroid cancer cells. Triptolide increased the mRNA expression of CDKN1A and TP53 but reduced the mRNA expression of c-JUN and RELA, as shown by RT-PCR. Triptolide increased the protein levels of CDKN1A and phospho-p53 but reduced those of phospho-c-JUN and phospho-NF-κB p65, as shown by Western blotting.. We considered that triptolide could treat thyroid cancer by inhibiting cell proliferation, inducing apoptosis and inhibiting inflammatory pathways such as the NF-κB and MAPK signaling pathways. CDKN1A, c-JUN, RELA, and TP53 were involved in the antithyroid cancer mechanism of triptolide.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Cell Line, Tumor; Diterpenes; Epoxy Compounds; Humans; MAP Kinase Signaling System; Molecular Docking Simulation; NF-kappa B; Phenanthrenes; Protein Interaction Maps; Thyroid Neoplasms

Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer and is responsible for 20‑50% of thyroid cancer‑associated deaths. The absence of response to conventional treatments makes the search for novel therapeutics a clinical challenge. In the present study, the effects of 15,16‑dihydrotanshinone I (DHT), a tanshinone extracted from

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Cisplatin; Drug Synergism; Drug Therapy, Combination; Furans; Gene Expression Regulation, Neoplastic; Humans; Phenanthrenes; Quinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

ATC is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. In patients without known genetic aberrations, the current treatment is still represented by palliative surgery and systemic mono- or combined chemotherapy, which is often not fully effective for the appearance of drug resistance. Comprehension of the mechanisms involved in the development of the resistance is therefore an urgent issue to suggest novel therapeutic approaches for this very aggressive malignancy. In this study, we created a model of anaplastic thyroid cancer (ATC) cells resistant to paclitaxel and investigated the characteristics of these cells by analyzing the profile of gene expression and comparing it with that of paclitaxel-sensitive original ATC cell lines. In addition, we evaluated the effects of Dihydrotanshinone I (DHT) on the viability and invasiveness of paclitaxel-resistant cells. ATC paclitaxel-resistant cells highlighted an overexpression of ABCB1 and a hyper-activation of the NF-κB compared to sensitive cells. DHT treatment resulted in a reduction of viability and clonogenic ability of resistant cells. Moreover, DHT induces a decrement of NF-κB activity in SW1736-PTX and 8505C-PTX cells. In conclusion, to the best of our knowledge, the results of the present study are the first to demonstrate the antitumor effects of DHT on ATC cells resistant to Paclitaxel in vitro.

Topics: Cell Line, Tumor; Cell Movement; Cell Survival; Drug Resistance, Neoplasm; Furans; Humans; NF-kappa B; Paclitaxel; Phenanthrenes; Quinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

The effec.t of BIIB021, a novel heat shock protein 90 (hsp90) inhibitor, on survival of thyroid carcinoma cells has not been evaluated. In this study, the impact of BIIB021 alone or in combination with the histone acetyltransferase inhibitor triptolide on survival of thyroid carcinoma cells was identified. In 8505C and TPC-1 thyroid carcinoma cells, BIIB021 caused cell death in conjunction with alterations in expression of hsp90 client proteins. Cotreatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, decreased cell viability, and increased the percentage of dead cells and cytotoxic activity. All of the combination index values were lower than 1.0, suggesting synergistic activity of BIIB021 with triptolide in induction of cytotoxicity. In treatment of both BIIB021 and triptolide, compared with treatment of BIIB021 alone, the protein levels of total and phospho-p53, and cleaved caspase-3 were elevated, while those of total Akt, phospho-mTOR, phospho-4EBP1, phospho-S6K, phospho-NF-κB, survivin, X-linked inhibitor of apoptosis protein (xIAP), cellular inhibitor of apoptosis protein (cIAP) and acetyl. histone H4 were reduced. These results suggest that BIIB021 has a cytotoxic activity accompanied by regulation of hsp90 client proteins in thyroid carcinoma cells. Moreover, the synergism between BIIB021 and triptolide in induction of cytotoxicity is associated with the inhibition of PI3K/Akt/mTOR and NF-κB signal pathways, the underexpression of survivin and the activation of DNA damage response in thyroid carcinoma cells.

Topics: Adenine; Apoptosis; Cell Line, Tumor; Cell Survival; Diterpenes; DNA Damage; Drug Synergism; Epoxy Compounds; HSP90 Heat-Shock Proteins; Humans; Inhibitor of Apoptosis Proteins; NF-kappa B; Phenanthrenes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Signal Transduction; Survivin; Thyroid Neoplasms; TOR Serine-Threonine Kinases

Since PARP-1 is supposed to be part of a multimeric repressor of sodium iodide symporter (NIS) expression, in this study the effect of the PARP inhibitor PJ34 on several properties of thyroid cancer cell lines was investigated. In TPC1, BCPAP, FRO, WRO cell lines PJ34 induced a strong increase in NIS mRNA levels. In BCPAP and TPC1 cells also significant increase of radio-iodine uptake was induced. Accordingly, in transfection experiments performed in TPC1 cells, treatment with PJ34 increased NIS promoter activity without affecting PARP-1 binding to the promoter sequence. We also investigated the epigenetic status of NIS promoter after PJ34 treatment in TPC1 cell line: in addition to an increase of histone modification activation marks (H3K9K14ac, H3K4me3), surprisingly we observed also an increase of H3K27me3, a classical repressive mark. Our data demonstrate that in various thyroid cancer cell lines PARP inhibition increases NIS gene expression through a particular modulation of transcriptional regulatory mechanisms. Therefore, we suggest that PARP inhibitors may deserve future investigations as tools for medical treatment of thyroid cancer.

Topics: Acetylation; Antineoplastic Agents; Biological Transport; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Iodine; Methylation; Neoplasm Proteins; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Promoter Regions, Genetic; Protein Processing, Post-Translational; RNA, Messenger; Symporters; Thyroid Neoplasms

Anaplastic thyroid carcinoma (ATC) is among the most aggressive malignancies known and is characterized with rapid growth, early invasion, and complete refractoriness to current therapies. Here we report that triptolide, a small molecule from a Chinese herb, could potently inhibit proliferation in vitro, angiogenesis in vivo, and invasion in a Matrigel model in human ATC cell line TA-K cells at nanomolar concentrations. We further elucidate that triptolide inhibits the nuclear factor-kappaB (NF-kappaB) transcriptional activity via blocking the association of p65 subunit with CREB-binding protein (CBP)/p300 in the early stage and via decreasing the protein level of p65 in the late stage. Expression of the NF-kappaB targeting genes cyclin D1, vascular endothelial growth factor, and urokinase-type plasminogen activator is significantly reduced by triptolide in both TA-K and 8505C human ATC cell lines, which are well known to be critical for proliferation, angiogenesis, and invasion in solid tumors. Our findings suggest that triptolide may function as a small molecule inhibitor of tumor angiogenesis and invasion and may provide novel mechanistic insights into the potential therapy for human ATC.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Carcinoma; Cell Line, Tumor; Diterpenes; Dose-Response Relationship, Drug; Down-Regulation; Epoxy Compounds; Humans; Neoplasm Invasiveness; Neovascularization, Pathologic; NF-kappa B; Phenanthrenes; Signal Transduction; Thyroid Neoplasms; Tripterygium

Triptolide, a traditional anti-inflammatory and anti-immunodepressive agent, has been reported to exert anti-neoplastic activity on several human tumor cell lines. This study investigates the pro-apoptotic function and the functional mechanism of triptolide on anaplastic thyroid carcinoma (ATC) cells. Experiments presented here demonstrated that triptolide had dose-dependent effects on cell viability of human ATC cell line TA-K cells through inducing cell apoptosis. In the molecular level, triptolide did not successfully initiate p53 signaling pathway, but downregulated the nuclear factor kappaB (NF-kappaB) pathway. Our studies suggest that triptolide functions as an effective apoptotic inducer in a p53-independent, but NF-kappaB-dependent mechanism, thus providing a promising agent for tumor types with p53 mutation/deletion.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Cell Line, Tumor; Cell Survival; Diterpenes; Dose-Response Relationship, Drug; Epoxy Compounds; Gene Deletion; Gene Expression Regulation, Neoplastic; Humans; Mutation; NF-kappa B; Phenanthrenes; Thyroid Neoplasms; Time Factors; Tumor Suppressor Protein p53