Abstract
Drug resistance of tumor cells is always a headache problem in clinical treatment. In order to combat chemotherapy-resistance in cervical cancer and improve treatment effect, we design a CRISPR/Cas9 nanoeditor to knock out two key oncogenes E6 and E7 that lead to drug tolerance. Meanwhile, the deletion of these two oncogenes can effectively reactivate p53 and pRB signaling pathways that inhibit the growth of tumor cells. Our results demonstrated the nanoeditor could simultaneously delete two oncogenes, and the size of DNA fragments knocked out reaches an unprecedented 563 bp. After the preparation of cationic liposomes combined with chemotherapy drug docetaxel (DOC), this nanosystem can significantly inhibit the drug tolerance of cancer cells and improve the therapeutic effect of cervical cancer. Therefore, this study provides a promising strategy for the treatment of cervical cancer by combining chemotherapy and double-target gene therapy. This strategy can also be applied in other disease models to customize personalized anti-tumor strategies by simply changing chemotherapy drugs and targeted genes.
Highlights
Chemotherapy is one of the most important strategies of cancer treatment [1]
After the oncogene was deleted, we found that the p53 and pRB signaling pathways which inhibit tumor cell growth were reactivated, which combined with docetaxel (DOC) and significantly improve the killing efficiency of cervical cancer cells
Construction of CRISPR/Cas9 plasmid to target the deletion of oncogenes Cervical cancer is mainly caused by human papilloma virus (HPV) infection [32], and the overexpression of E6 and E7 oncogenes in HPV infected cervical cancer cells is the key to maintain the growth and proliferation of cancer cells [33, 34]
Summary
Chemotherapy is one of the most important strategies of cancer treatment [1]. Chemo-resistance continues to be the principal limiting factor to achieving cures in patients with cancer [2]. Evidence shows that even when chemotherapy causes tumors remission quickly, while drug resistance would appear in the course of long-term drug use, which leads to the failure of tumor treatment [3,4,5]. The interaction between drug and tumor microenvironment is very complex which affects each other throughout. Property of cancer cells develops remarkable resistance to various treatments which target different molecular pathways [8,9,10].
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