Imatinib Enhances Docetaxel-Induced Apoptosis Through Inhibition of Nuclear Factor-κB Activation in Anaplastic Thyroid Carcinoma Cells

Abstract

Background: We previously reported the partial effectiveness of imatinib (also known as STI571, Glivec, or Gleevec) on anaplastic thyroid cancer (ATC) cells. Imatinib is a selective tyrosine kinase inhibitor that has been used for various types of cancer treatments. Recently, several reports have demonstrated that imatinib enhanced the sensitivity of cancer cells to other anticancer drugs. In this study, therefore, we investigated whether imatinib enhances the antitumor activity of docetaxel in ATC cells. Methods: Two ATC cell lines, FRO and KTC-2, were treated with imatinib and/or docetaxel. Cell survival assay and flow cytometry for annexin V were used to assess the induction of apoptosis. Changes of pro-and antiapoptotic factors were determined by Western blot. Nuclear factor-jB (NF-jB) activity was measured by DNAbinding assay. Tumor growth was also investigated in vivo. Results: The combined treatment significantly enhanced apoptosis compared with single treatment. ATC cells themselves expressed high levels of antiapoptotic factors, X-linked inhibitor of apoptosis (XIAP), and survivin. The treatment with docetaxel alone further increased their expressions; however, the combined treatment blocked the inductions. Although imatinib alone had no effect on NF-jB background levels, combined treatment significantly suppressed the docetaxel-induced NF-jB activation. Further, the combined administration of the drugs also showed significantly greater inhibitory effect on tumor growth in mice xenograft model. Conclusions: Imatinib enhanced antitumor activity of docetaxel in ATC cells. Docetaxel seemed to induce both pro-and antiapoptotic signaling pathways in ATC cells, and imatinib blocked the antiapoptotic signal. Thus, docetaxel combined with imatinib emerges as an attractive strategy for the treatment of ATC.

Co-delivery of dihydroartemisinin and docetaxel in pH-sensitive nanoparticles for treating metastatic breast cancerviathe NF-κB/MMP-2 signal pathway

“…Thus, D/D NPs are expected to effectively treat metastatic breast cancer, with evidence supporting the synergistic effects of the combination of DTX and DHA in treating metastatic breast cancer. In our study of the mechanism of D/D NPs in antimetastasis, we identied from previous research that DTX regulates the expression of NF-kB to inhibit cancer cell proliferation, 40 while DHA could also inuence the expression of NF-kB, via the AKT/NF-kB or NF-kB/GLUT1 pathway. 41 Our data suggested that the combination of DTX and DHA decreased the expression of NF-kB more than free DTX did.…”

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

“…DTX is widely used as a cancer treatment (6)(7)(8)(9)(10)(11)(12)(13)(14). However, the emergence of chemotherapeutic resistance iTHs universal and DTX-resistance responses have been observed in a number of patients (15).…”

“…Docetaxel (DTX) is a well-established anti-mitotic chemotherapy agent that functions by interfering with cell division (5). It is used to treat a number of cancer types including metastatic or advanced breast, prostate, thyroid, gastric, ovarian and lung cancer based on its pro-apoptosis potential and its inhibitory effect on angiogenesis and cell viability (6)(7)(8)(9)(10)(11)(12)(13)(14). DTX has also been demonstrated to upregulate growth/differentiation factor 15 and results in chemoresistance in prostate cancer (15).…”

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience

“…Another way of overcoming drug resistance mechanism and/or enhancing drug efficacy is the combination of TKIs or other target agents with chemotherapy or radiotherapy. In fact, it has been demonstrated that treatment with BEZ235 and paclitaxel, imatinib and docetaxel, and efatutazone, a PPARγ agonist, and paclitaxel have synergistic effects in vitro compared to the effect of treatment with a single agent (Copland et al 2006, Kim et al 2012. These combinations were demonstrated to be safe and tolerable in ATC patients in a phase 1 trial .…”