Abstract

The major obstacle of successful tumor treatment with carboplatin (CBP) is the development of drug resistance. In the present study, we found that following treatment with CBP the amount of platinum which enters the human laryngeal carcinoma (HEp2)-derived CBP-resistant (7T) cells is reduced relative to the parental HEp2. As a consequence, the formation of reactive oxidative species (ROS) is reduced, the induction of endoplasmic reticulum (ER) stress is diminished, the amount of inter- and intrastrand cross-links is lower, and the induction of apoptosis is depressed. In HEp2 cells, ROS scavenger tempol, inhibitor of ER stress salubrinal, as well as gene silencing of ER stress marker CCAAT/enhancer-binding protein (CHOP) increases their survival and renders them as resistant to CBP as 7T cell subline but did not influence the survival of 7T cells. Our results suggest that in HEp2 cells CBP-induced ROS is a stimulus for ER stress. To the contrary, despite the ability of CBP to induce formation of ROS and activate ER stress in 7T cells, the cell death mechanism in 7T cells is independent of ROS induction and activation of ER stress. The novel signaling pathway of CBP-driven toxicity that was found in the HEp2 cell line, i.e. increased ROS formation and induction of ER stress, may be predictive for therapeutic response of epithelial cancer cells to CBP-based therapy.

Highlights

  • Carboplatin (cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II); CBP) is an important drug used to treat different types of epithelial tumors [1,2,3]

  • Protection of 7T cells from apoptosis following treatment with CBP was confirmed upon treatment of HEp2 and 7T cells with 40 mg/mL CBP for 24–48 h (Fig. 1A, lower figure)

  • reactive oxidative species (ROS) formation was significantly increased as early as 1.5 h after treatment with CBP in parental HEp2 cells, while the CBP-mediated increase in ROS formation in CBPresistant 7T cells was first detected 6 h after CBP treatment. These results suggest that CBP causes ROS formation very early after treatment in HEp2 cells and that the generation of ROS is diminished in the HEp2-derived CBP-resistant 7T cell subline, probably due to decreased accumulation of platinum in 7T cells

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Summary

Introduction

Carboplatin (cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II); CBP) is an important drug used to treat different types of epithelial tumors [1,2,3]. Several molecular mechanisms have been described to be involved in CBP resistance: (a) diminished drug accumulation, (b) elevated drug inactivation, (c) DNA repair or elevated DNA damage tolerance, (d) enhanced expression of anti-apoptotic genes, and (e) inactivation of the p53 pathway (all reviewed in [5,7]). None of these molecular mechanisms was found to be the single dominant factor determining CBP resistance. CBP resistance is a result of multiple mechanisms activated in parallel upon drug treatment

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