Effects of Dihydrotanshinone I on Proliferation and Invasiveness of Paclitaxel-Resistant Anaplastic Thyroid Cancer Cells

Abstract

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.

GSK2801 Reverses Paclitaxel Resistance in Anaplastic Thyroid Cancer Cell Lines through MYCN Downregulation

“…Since in a previous study, mRNA-seq analysis had shown expression of GSK2801 targets ( BAZ2A, BAZ2B and BRD9 ) in SW1736 and 8505C paclitaxel-resistant cells [ 3 ], we wondered whether these bromodomain protein actions represent a mechanism of resistance to taxane treatment in this model. Figure 1 shows that in paclitaxel-resistant ATC cells (8505C-PTX and SW1736-PTX), the expression level of BRD9 is increased compared with non-resistant parental lines both at the mRNA and protein levels ( Figure 1 , panel A and C).…”

“…Our research group has been moving for years in the field of studying new therapeutic agents that can cope with the progression of ATC [ 37 ]. After experimenting with natural compounds, among others, we generated two cell lines resistant to paclitaxel treatment, derived from two anaplastic thyroid cancer cell lines (SW1736 and 8505C) [ 3 ]. Paclitaxel indeed, is a taxane still indicated in mono- or multi-therapy for those tumors in which the molecular signature does not suggest the use of personalized treatment with a tyrosine kinase inhibitor [ 4 ].…”

“…Paclitaxel indeed, is a taxane still indicated in mono- or multi-therapy for those tumors in which the molecular signature does not suggest the use of personalized treatment with a tyrosine kinase inhibitor [ 4 ]. In our previous studies, we obtained interesting results regarding the gene expression profile of paclitaxel-resistant ATC cells compared with susceptible cells; moreover, we had already demonstrated the role of bromodomain and extra-terminal (BET) proteins and their inhibitors in this tumor type [ 3 , 38 , 39 ]. Therefore, we focused our attention on three genes coding for bromodomain-containing proteins (BAZ2A, BAZ2B, and BRD9) that were all expressed in paclitaxel-resistant SW1736 and 8505C cancer cell lines.…”

“…In fact, although it accounts for a very small percentage of all thyroid malignancies (less than 2%), it is mostly diagnosed as stage IV disease, is often unresectable, and fails to respond to radioactive iodine ablation because of its undifferentiated phenotype due to loss of thyroid-specific gene expression. Therefore, ATC is responsible for 20–50% of thyroid cancer mortality [ 3 ]. Stage IVA and IVB (when resectable) ATCs are treated by surgical resection followed by intensity-modulated radiation therapy (IMRT) and taxane-based chemotherapy alone or in combination with platinum or anthracycline [ 4 ].…”

Parthenolide leads to proteomic differences in thyroid cancer cells and promotes apoptosis

“…Recent studies have shown that PTL inhibit the skeletal NF-κB signaling pathway to reduce prostate cancer related osteolysis [ 32 ]. A recent study have demonstrated that Dihydrotanshinone I, a tanshinone extracted from Salvia miltiorrhiza Bunge , can induce a decrement of NF-κB activity in anaplastic thyroid cancer paclitaxel-resistant cells SW1736-PTX and 8505C-PTX, resulting in decreased viability and clonogenic ability of the resistant cells [ 33 ]. Therefore, the effect of PTL on thyroid cancer may also be affected by targeting NF-κB pathway, further research is needed to confirm that.…”