Cellular sensitization to cisplatin and carboplatin with decreased removal of platinum-DNA adduct by glucose-regulated stress.

Abstract

Stress conditions, such as glucose starvation and hypoxia, that induce glucose-regulated proteins (GRPs) in cells, are seen in most solid tumors. These conditions have been shown to cause cellular resistance to multiple anticancer drugs, such as etoposide, doxorubicin, and camptothecin. We examined the effect of the GRP-inducing conditions on cellular sensitivity to cisplatin and carboplatin, which are widely used drugs against solid tumors. We generated the GRP-inducing culture conditions by exposing cells to 2-deoxyglucose (2DG), calcium ionophore A23187 and tunicamycin, and examined cellular sensitivity to cisplatin and carboplatin under these conditions. We next measured platinum accumulation and DNA-bound platinum in 2DG-stressed cells after cisplatin exposure. The GRP-inducing stress conditions led to cellular sensitization to cisplatin and carboplatin. This sensitization was reversible, as the cellular sensitivity returned to normal levels 12 h after removal of 2DG. Platinum accumulation and DNA-bound platinum that were found immediately after exposure to cisplatin for 1 h were slightly increased in 2DG-stressed cells as compared with nonstressed cells. After a drug-free recovery incubation of 8 h, the DNA-bound platinum in the nonstressed cells was reduced by 33% while the amount in the 2DG-stressed cells was sustained at the initial levels. These results indicated that the decreased removal of platinum-DNA adducts was associated with increased sensitivity to cisplatin and carboplatin in the stressed cells. The sensitization of cancer cells under the GRP-inducing stress conditions would explain, in part, the clinical potency of platinum drugs against solid tumors.