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The Antitumor Efficiency of Zinc Finger Nuclease combined with Cisplatin and Trichostatin A in Cervical Cancer Cells.

BACKGROUND
Persistent infection with the high-risk human papillomavirus (HR-HPVs) were the primary etiological factor of cervical cancer, HR-HPVs express oncoproteins E6 and E7, both of which play key roles in the progression of cervical carcinogenesis. Zinc Finger Nucleases (ZFNs) targeting HPV E7 induce specific shear of the E7 gene, weakening the malignant biological effects, hence showing great potential for clinical transformation.


OBJECTIVE
Our aim was to develop a new comprehensive therapy for better clinical application of ZFNs. We here explored the anti-cancer efficiency of HPV targeted ZFNs combined with a platinum-based antineoplastic drug Cisplatin (DDP) and a HDAC inhibitor trichostatin A (TSA).


METHODS
SiHa and HeLa cells were exposed to different concentrations of DDP and TSA, the appropriate concentrations for the following experiments were screened according to cell apoptosis. Then cells were grouped for combined or separate treatments, the apoptosis、cell viability and proliferation ability was measured by flow cytometry detection、CCK-8 assays and colony formation assays. The xenograft experiments were also performed to determine the anti-cancer effects of the combined therapy. In addition, the HPV E7 and RB1 expression was measured by western blot analysis.


RESULTS
Results showed that the combined therapy induced about two times more apoptosis than that of ZFNs alone in SiHa and HeLa cells, and much more inhibition of cell viability than either of the separate treatment. The colony formation ability was inhibited more than 80% by the co-treatment, the protein expression of HPV16/18E7 was down regulated and that of RB1 was elevated. In addition, the xenografts experiment showed a synergistic effect between DDP and TSA together with ZFNs.


CONCLUSION
Our results demonstrated that ZFNs combined with DDP or TSA functioned effectively in cervical cancer cells, and it provided novel ideas for the prevention and treatment of HPV-related cervical malignances.