Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy
Waleed M. Abuzeid, … , Bert W. O’Malley Jr., Daqing Li
Waleed M. Abuzeid, … , Bert W. O’Malley Jr., Daqing Li
Published June 1, 2009
Citation Information: J Clin Invest. 2009;119(7):1974-1985. https://doi.org/10.1172/JCI33816.
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Research Article Oncology

Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy

Abstract

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.

Authors

Waleed M. Abuzeid, Xiaoling Jiang, Guoli Shi, Hui Wang, David Paulson, Koji Araki, David Jungreis, James Carney, Bert W. O’Malley Jr., Daqing Li

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Figure 7

Ad-RAD50 chemosensitizes JHU012 human head and neck cancer to cisplatin in vivo.

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Ad-RAD50 chemosensitizes JHU012 human head and neck cancer to cisplatin ...
(A) Externally measured tumor volume ± SEM from the time of initial tumor palpability on day 4, to treatment initiation on day 13, and through the treatment period to day 20. (B) Mean internally measured tumor volume ± SEM immediately prior to treatment on day 13 and at the time of animal sacrifice on day 24. (C) Mean internally measured change in tumor volume ± SEM. During the 11 day period between treatment initiation and animal sacrifice, a single administration of Ad-RAD50 combined with a single intraperitoneal dose of cisplatin, at either 3 mg/kg or 5 mg/kg, was able to significantly enhance the therapeutic efficacy of cisplatin (3 mg/kg or 5 mg/kg) monotherapy. For Ad-RAD50 with cisplatin (3 mg/kg), P < 0.001 vs. control; P < 0.05 vs. cisplatin (3 mg/kg) and cisplatin (5 mg/kg) with DL312; and P < 0.05 vs. Ad-RAD50 alone. For Ad-RAD50 with cisplatin (5 mg/kg), P < 0.001 vs. control, cisplatin (3 mg/kg), cisplatin (5 mg/kg) with DL312, and Ad-RAD50 alone.