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Anaplastic thyroid carcinoma ATC although rare is the most deadly form of thyroid cancer. Control of ATC is severely hard and widespread with unpredictability.
We Previous proved that histone gene reviser and epigenetic changes role significant parts in papillary and anaplastic thyroid cancer tumorigenesis. Herein, the goal of this study was to investigate the buup activities of a HDAC inhibitor, HNHA alone and in combination with sorafenib in ATC cells in vitro and in vivo and to explore its effects on apoptotic cell death pathways.
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Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis.
The ATC 310 lines xenograft model was used to examine the anti-tumor activity in vivo.
Our data showed that HNHA and sorafenib synergistically decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as proved by the cleavage of caspase-3 and DNA fragmentation. Thus, combination therapy with HNHA and sorafenib significantly decreased vessel density, and most significantly reduced tumor volume and increased survival in ATC xenografts. These results propose that HNHA in combination with sorafenib has significant anti-cancer activity in preclinical models, potentially suggesting a new clinical approach for patients of advanced thyroid cancer type.
A significant event in the tumorigenic transformation of thyroid follicular cells is the constitutive stimulation of a single signaling pathway. Patients with the most ordinary type of thyroid cancer, PTC, have low hazard of recurrence and high survival. However, some patients with ATC exhibit high levels of invasiveness and metastasis, and do not respond to any chemotherapy, typically dying in a few months .
Some HDAC inhibitors are currently in clinical trials as therapeutic agents alone or in combination with other anticancer drugs . N -hydroxy 2-naphthylthio hepatonomide HNHA is a novel HDAC inhibitor that demonstrates significantly higher anticancer activity than other HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid . Sorafenib is a multi-kinase inhibitor that obstructs different signaling pathways, including Raf kinases, vascular endothelial growth factor receptor VEGFRand platelet-derived growth factor receptors PDGFRs .
Furthermore, sorafenib has also been approved for the therapy of advanced renal cell carcinoma RCC and various other human cancers, including thyroid cancer .
Like HDAC inhibitors, sorafenib suppresses tumorigenesis by translationally restraining the anti-apoptotic Bcl-2 family member, Mcl-1 . Recently, Stat3 was shown to be a major kinase-independent target of sorafenib . Unfortunately, however, a majority of the patients does not respond to sorafenib and HDAC inhibitors, and several patients who initially do respond subsequently become resistant, with the continuation of tumor progression .
Consequently, several researchers have sought to target human cancer with a combination of sorafenib and chemotherapy . Since most patients with ATC are diagnosed at an advanced stage, there is a desperate need for new cancer therapies. The tumor tissue were acquired during surgical resection of primary and metastatic ATC sites. After resection, tumors were kept in normal saline with ubp and antibiotic agents.
Cell viability was analyzed by the trypan blue dye exclusion method.
Authentication was performed by short tandem repeat profiling, karyotyping, and isoenzyme analysis. Cell line characteristics, viability after drug treatment of all thyroid carncer cell lines examined. Cells were then incubated for the indicated time points before the determination of cell viability, using the MTT reagent according to the manufacturer’s protocol, and absorbance was measured at nm.
This experiment was repeated thrice, and the results were averaged. The apoptotic cells fluorescent green and total cells were counted by fluorescence microscopy. The antibodies for p53 and p21 were obtained from Abcam Cambridge, UK. Human ATC cells 2.
Tumor size was measured every other day using calipers. Tumor volume was estimated using the following formula: Animals were maintained under specific pathogen-free conditions. Six-week-old mice were caged for 1 week for acclimatization. The animals were monitored regularly for external signs of toxicity or lethality. A standard diet of rodent pellets and tap water membrane filter-purified and autoclaved were provided ad libitum. All 3410 sections were counterstained with hematoxylin, dehydrated, and mounted.
Further characterization of the synergistic effect of HNHA and sorafenib on ATC cell viability showed that the combination reduced the viability of ATC bul to a greater extent than by either agent alone. All experiments were repeated at least 3 times. Experiments were repeated at least 3 times with similar results. IC50 half maximal inhibitory concentration determination using a cell proliferation assay. Flow cytometry was performed to investigate the effects of these compounds on cell cycle progression.
Combination of HNHA and sorafenib induced cell cycle arrest and endoplasmic reticulum stress in ATC cells more potently than either agent alone.
Immunoblot bbup of the indicated cell lines following exposure to the HNHA and sorafenib combination or each agent singly. The HNHA and sorafenib combination potently induced the expression of cell cycle arrest proteins and reduced the expression of positive regulators of the 314 cycle A.
Cells were exposed to the indicated inhibitors, harvested, and stained with propidium iodide before analysis by flow cytometry and FlowJo v8 software C. These data demonstrated that the synergistic effect of HNHA and sorafenib efficiently induces apoptosis in ATC cells and that it exerts this effect via caspase cleavage and inhibition of the Bcl-2 pathway.
Immunoblot analyses suggested that the indicated inhibitors increased the levels of apoptotic proteins and reduced those of anti-apoptotic proteins in ATC cells A.
Mouse survival was prolonged significantly by both agents, but their combination yielded better survival rates Figure 4B bupp, F buo, and J. No evidence of systemic toxicity or treatment-related death was found in any group.
The combination-treated group showed significantly smaller tumor volumes compared to the groups treated with HNHA or sorafenib alone Figure 4DHand L.
This implies a more efficient bupp of cell cycle arrest and apoptosis due to ER stress in ATC mouse xenografts by the combination treatment Figure 4 M.
Athymic nude mice with established tumors were treated with the indicated inhibitors.
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Data represent the mean tumor volumes. The compounds had no significant effect on mouse body weight C, G, and K. Weights of the dissected tumors D, H, and L. Immunoblot analysis of total proteins isolated from the tumors M.
Anti-apoptotic activity is an important factor in the assessment of the biological behavior of tumorigenesis. At present, Bcl-2 is the most useful marker of anti-apoptosis. We detected this marker by immunohistochemical examination of C, SNU, and GSA1 cell xenograft tumors and found that the combination-treated group showed the strongest decrease in Bcl-2 expression Figure 5A — Cfurther confirming that HNHA and sorafenib combination 310 has potent anticancer activity in the ATC xenograft model.
HNHA and sorafenib combination therapy significantly reduced tumor Bcl-2 expression. Immunohistochemical analysis of the Bcl-2 protein levels in paraffin-embedded tumor tissues from mice with ATC xenografts.
Thyroid cancer is a common endocrine malignancy . Recent times have witnessed dramatic improvements in the perception of the molecular pathogenesis of this cancer, best explained by the essential roles of certain signaling pathways. The key mechanisms are epigenetic and genetic modifications in these pathways, such as uncontrolled methylation and mutation of bu; .
A great number of these molecular modifications provide clues about novel bul and diagnostic 33140 targets bu; thyroid cancer, thereby providing immense chances for further study and progress in the development of novel treatment strategies for this cancer. However, in thyroid carcinomas, the pathways and molecules connected to the effect of BRAF suppression bpu cellular survival are poorly understood.
Notably, patients with PTC have a low risk of recurrence and high survival, whereas some patients with ATC show considerable metastasis and respond poorly to chemotherapy .
Therefore, combinations of targeted therapies that shrink ATCs are warranted. HDACs are histone-modifying enzymes that play major roles in the control of several proteins that are involved in tumorigenesis. Deviant expression of some HDACs has been demonstrated in diverse human cancers . High HDAC1 expression has been linked with a more advanced tumor—node—metastasis stage, greater cancer cell invasion, and a lower survival rate in human cancers bip.
Accordingly, Byp are promising drug targets for treating several human cancers. Some HDAC inhibitors are being investigated for their effects against solid and hematologic malignancies . HDAC inhibitors are also being assessed in combination with radiotherapy, chemotherapy, and molecular targeted agents .
One study proved that patients with high levels of p-Erk have a greater survival rate . The use of this multi-kinase inhibitor was bkp permitted for the therapy of advanced thyroid cancer .
The mechanisms underlying these synergistic anticancer effects of both agents on ATC 31440 lines included the induction of cell cycle arrest and apoptosis. Apoptosis was shown by the increased proportion of cells in sub-G 1 and by the stimulation of caspase 3. The combination therapy also demonstrated a characteristic effect on cell cycle progression, whereby G 1 arrest was evident in the presence of lower concentrations of HNHA and sorafenib, as compared to the levels of HNHA or sorafenib that individually produced this effect.
This finding was consistent with those of previous studies showing that HNHA or sorafenib when used alone are cytotoxic and induce G 1 arrest at lower concentrations . Consistent with this, the capacity of HDAC inhibitors to induce p21 expression has been described in a number of cell types and has been shown to occur through promoter hyperacetylation .
The inhibition of p21 expression affects the lethality of HDAC inhibitors and DNA-damaging agents in various cancer cell types, such as leukemia, thyroid cancer, and RCC . It has been suggested that p21 is cleaved by caspase-3 for DNA injury-mediated apoptosis . Sorafenib-mediated transcriptional suppression may cause the down-regulation of p Besides its role as a cyclin-mediated kinase inhibitor, some investigations propose that p21 might engage in DNA repair by controlling the interaction between PARP-1 and base excision repair factors, thereby participating in resistance to chemotherapeutic agents .
Therefore, it will be interesting to investigate whether the sorafenib-mediated down-regulation of p21 causes the synergistic interaction between HNHA and sorafenib.
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The authors thank Dr. Seung Won Kim for critical brainstorming and Dr. Kyung Hwa Choi for assistance with tumor cell isolation from patient specimen. National Center for Biotechnology InformationU. Journal List Neoplasia v.
Published online Jan Author information Article notes Copyright and License information Disclaimer. This article has been corrected. This article has been cited by other articles in PMC. Abstract Anaplastic thyroid carcinoma ATC although rare is the most deadly 310 of thyroid cancer. Introduction A significant event in the tumorigenic transformation of thyroid follicular cells is the constitutive stimulation of a single signaling pathway.