Kim, Seok-Mo1, Park, Ki-Cheong1, Kim, Soo Young1, Chang, Hojin1, Kim, Bup-Woo1, Lee, Yong Sang1, Chang , Hang-Seok1, Park, Cheong Soo1
1 Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
Background: Anaplastic thyroid carcinoma (ATC) is the most deadly form of thyroid cancer. The goal of this study was to investigate the anti-tumor activities of paclitaxel with radiation and in combination with tyrosine kinase inhibitors(TKI) in ATC cells in vitro and in vivo and to explore its effects on apoptotic cell death pathways.
Methods: Three ATC cell lines were exposed to TKI in the presence or absence of paclitaxel with radiation and cell viability was determined by MTT assay. Effects of combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell lines xenograft model was used to examine the anti-tumor activity in vivo.
Results: Our data showed that paclitaxel with radiation and TKIS 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. Paclitaxel and TKI with radiation combination was reduced anti-apoptotic factor in ATC. Thus, TKI that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and -3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. Combination therapy with paclitaxel and TKI with radiation significantly decreased vessel density, and most significantly reduced tumor volume and increased survival in ATC xenografts.
Conclusions: These results propose that paclitaxel and TKI with radiation has significant anti-cancer activity in preclinical models, potentially suggesting a new clinical approach for patients of advanced thyroid cancer type.