Correlation Study Of RRM1and RRM2Expression And Cervical Cancer Chemotherapy

Background: Ribonucleotide reductase (RR) is the rate limiting enzyme for DNA replicationand repair in all living cells, it plays a significant role in the regulation of cell proliferation, cellmigration and tumor metastasis. Cervical cancer, as a second leading cause of cancer death inwomen worldwide, and chemotherapy becomes an important method for treatment. Severalchemotherapeutic agents target RR. At present, gemcitabine is the most potent and most widelyused RR inhibitor. The present study aims to investigate the subunits expression and enzymeactivity of ribonucleotide reductase (RR) in cervical cancer tissues and cell lines, and detect thecombined effect of the RR inhibitor gemcitabine and the chemotherapeutic agent carboplatin oncervical cancer cell lines.Methods: Using quantitative reverse transription polymerase chain reaction(qRT-PCR),Western blotting and CDP reduction assays, we tested the expression and activity of RR in cervicalcancer patients. The antitumor activity of GEM and/or CBDCA treatments to Siha and Caskihuman cervical cancer cell lines were assessed by CCK-8viability assay, EdU incorporation assay,immunofluorescence assay, flow cytometry assay and Western blotting methods. Moreover, thesynergistic efficacy between GEM and CBDCA was quantitatively analyzed using combinationindex (CI) based on the Chou-Talalay method.Results: The mRNA levels of RRM1and RRM2were all increased in the cervical cancertissues when compared with the normal tissues (P<0.0001). Consistently, the protein expressionand enzyme activity of RR were also increased in the cervical cancer tissues. Interestingly,gemcitabine inhibited DNA synthesis and carboplatin induced DNA damage, respectively.Furthermore, the combined drug regime had a significantly synergistic effect on inhibiting cervicalcancer cell viability (log10(CI)<0) through enhancing DNA damage and cell apoptosis.Conclusion: The expression and activity of RR were increased in cervical cancer. Our studydemonstrated the synergistic cytotoxicity of gemcitabine and carboplatin, via inhibiting DNAsynthesis and increasing cell apoptosis in cervical cancer cell lines. This evidence might provide arational clue of their combined application to improve cervical cancer treatment.