Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy.
Platinum-based drugs that induce DNA damage are commonly used first-line chemotherapy agents for testicular, bladder, head and neck, lung, esophageal, stomach, and ovarian cancers. The inherent resistance of tumors to DNA damage often limits the therapeutic efficacy of these agents, such as cisplatin. An enhanced DNA repair and telomere maintenance response by the Mre11/Rad50/Nbs1 (MRN) complex is critical in driving this chemoresistance. We hypothesized therefore that the targeted impairment of native cellular MRN function could sensitize tumor cells to cisplatin. To test this, we designed what we believe to be a novel dominant-negative adenoviral vector containing a mutant RAD50 gene that significantly downregulated MRN expression and markedly disrupted MRN function in human squamous cell carcinoma cells. A combination of cisplatin and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage and telomere shortening. In cisplatin-resistant human squamous cell cancer xenografts in nude mice, this combination therapy caused dramatic tumor regression with increased apoptosis. Our findings suggest the use of targeted RAD50 disruption as what we believe to be a novel chemosensitizing approach for cancer therapy in the context of chemoresistance. This strategy is potentially applicable to several types of malignant tumors that demonstrate chemoresistance and may positively impact the treatment of these patients.
Abuzeid
Waleed M
WM
Department of Otorhinolaryngology - Head and Neck Surgery, University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania 19104, USA.
Jiang
Xiaoling
X
Shi
Guoli
G
Wang
Hui
H
Paulson
David
D
Araki
Koji
K
Jungreis
David
D
Carney
James
J
O'Malley
Bert W
BW
Li
Daqing
D
D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000032:analysis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019281:Dimerization; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000032:analysis; D016615:Telomere; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes; D002945:Cisplatin