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Hypersensitivity to DNA Cross-linking Agents Associated with Up-Regulation of Glucose-regulated Stress Protein GRP78¹

Hematology/Oncology Division, Department of Medicine, and Cancer Research Center, Case Western Reserve University, Cleveland, Ohio 44106-4937

We have shown previously that NAD/poly(ADP-ribose) polymerase-deficient cells that overexpress M_r 78,000 glucose-regulated stress protein (GRP78) are resistant to topoisomerase II inhibitors, such as etoposide, m-amsacrine, and doxorubicin. However, these cells have been found to be hypersensitive to DNA cross-linking agents, including melphalan, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These observations prompted us to examine whether overexpression of GRP78 is associated with modulation of cytotoxicity of clinically useful DNA-cross-linking agents such as melphalan, BCNU, and cisplatin. We up-regulated GRP78 in V79 Chinese hamster cells by 2–5-fold using two independent approaches that include exposure to 6-aminonicotinamide, or 2-deoxyglucose. Subsequently, these GRP78-overexpressing cells were trypsinized, plated in regular medium without GRP78-inducing agents, and allowed a 5-h attachment time before being treated with melphalan, BCNU, or cisplatin for 1 h to determine clonogenic survivals. In addition, repair of DNA cross-links induced by those agents were determined by alkaline elution assay. Our results show that the GRP78-overexpressing V79 cells are hypersensitive to DNA cross-linking agents compared to the control V79 cells. Furthermore, repair of drug-induced DNA cross-links appears to be considerably slower in these cells relative to that found in control V79 cells. Thus, our results suggest that (a) up-regulation of GRP78 is associated with an impairment of DNA cross-link repair, (b) up-regulation of GRP78 is associated with potentiation of cytotoxicity induced by alkylating and platinating agents, and (c) up-regulation of GRP78 can be considered as a potentially useful tool to modulate the cytotoxicity of clinically useful alkylating and platinating agents.

¹ These studies were supported in part by National Cancer Institute Grants R29CA65920, PO1 CA51183, P30 CA43703, and UO1 CA63200.

² To whom requests for reprints should be addressed, at BRB 301, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4937. Phone: (216) 368-2825 and (216) 368-1175; Fax: (216) 368-1166.

Received 8/29/97. Accepted 9/17/97.

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