Abstract
RRM1—an important DNA replication/repair enzyme—is the primary molecular gemcitabine (GEM) target. High RRM1-expression associates with gemcitabine-resistance in various cancers and RRM1 inhibition may provide novel cancer treatment approaches. Our study elucidates how RRM1 inhibition affects cancer cell proliferation and influences gemcitabine-resistant bladder cancer cells. Of nine bladder cancer cell lines investigated, two RRM1 highly expressed cells, 253J and RT112, were selected for further experimentation. An RRM1-targeting shRNA was cloned into adenoviral vector, Ad-shRRM1. Gene and protein expression were investigated using real-time PCR and western blotting. Cell proliferation rate and chemotherapeutic sensitivity to GEM were assessed by MTT assay. A human tumor xenograft model was prepared by implanting RRM1 highly expressed tumors, derived from RT112 cells, in nude mice. Infection with Ad-shRRM1 effectively downregulated RRM1 expression, significantly inhibiting cell growth in both RRM1 highly expressed tumor cells. In vivo, Ad-shRRM1 treatment had pronounced antitumor effects against RRM1 highly expressed tumor xenografts (p < 0.05). Moreover, combination of Ad-shRRM1 and GEM inhibited cell proliferation in both cell lines significantly more than either treatment individually. Cancer gene therapy using anti-RRM1 shRNA has pronounced antitumor effects against RRM1 highly expressed tumors, and RRM1 inhibition specifically increases bladder cancer cell GEM-sensitivity. Ad-shRRM1/GEM combination therapy may offer new treatment options for patients with GEM-resistant bladder tumors.
Highlights
Introduction published maps and institutional affilBladder cancer is the most common malignancy of the urinary tract and the 10th leading cause of malignancy worldwide [1]
(IC50 : drug concentration growth by mu tiplicity of infection (MOI), multiplicity of infection; GEM: gemcitabine; CDDP: cisplatin). that inhibited cell growth by 50%; MOI, multiplicity of infection; GEM: gemcitabine; CDDP: cisplatin)
Reid et al verified that RRM1 silencing more effective in inhibiting cell growth than RRM2 silencing [22]
Summary
Introduction published maps and institutional affilBladder cancer is the most common malignancy of the urinary tract and the 10th leading cause of malignancy worldwide [1]. Up to 75% of bladder cancers appear as frequently recurring non-muscular invasive tumors, and 15–30% of them progress to muscle-invasive cancers [2]. Radical cystectomy (RC) is the mainstay therapy for patients with muscle-invasive cancers [3]. Despite well-performed surgeries, cure rates with surgery alone are only between 52.0% and 72.9%, for organ-confined disease [4,5]. With progression to metastatic bladder cancer, systemic chemotherapy is considered the standard treatment. Gemcitabine (GEM)—an effective cytotoxic drug—was approved for the treatment of various solid tumors [6]. Combination chemotherapy with GEM and cisplatin (CDDP), exhibiting higher activity and fewer adverse effects, is a first-line treatment for patients with metastatic bladder cancer [7]. While the initial response to combination chemotherapy is high, long-term progression-free and overall survival rates iations
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