Role of Reactive Oxygen Species in the Cytotoxicity of Arsenic Trioxide and Pamidronate for Human Prostate Cancer Cells

  • James H. Doroshow Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; City of Hope National Medical Center, Duarte, CA 91010, USA
  • Shikha Gaur City of Hope National Medical Center, Duarte, CA 91010, USA
Keywords: Arsenic trioxide; Bisphosphonates; Epidermal growth factor receptor; Pamidronate; Prostate cancer; Protein tyrosine phosphatase; Reactive oxygen species; Signal transduction

Abstract

To examine whether combining arsenic trioxide (ARS) and pamidronate (PAM), anticancer drugs that generate reactive oxygen species (ROS), enhanced targeting of redox sensitive growth signals, we studied cloning efficiency, protein tyrosine phosphatase (PTPase) activity, and epidermal growth factor receptor (EGFR) phosphorylation in DU-145 and PC-3 human prostate cancer cells in response to treatment with ARS and/or PAM for 24 h. IC50 concentrations in a clonogenic assay for ARS and PAM were 9 and 20 μM, respectively, in DU-145 cells; and 2 and 12 μM, in PC-3 cells. When combined, ARS and PAM demonstrated additive cytotoxicity in the DU-145 line (combination index [CI] of 1.10) and synergy for PC-3 cells (CI of 0.86). ARS (20 μM for 24 h) inhibited PTPase activity by 36 ± 7 %, p < 0.05 vs. untreated controls, in DU-145 cells; and by 58 ± 8%, p < 0.05, in the PC-3 line. PAM (20 μM for 24 h) decreased PTPase activity by 24 ± 9%, p= 0.06, and 8 ± 1%, p < 0.01, in DU-145 and PC-3 cells, respectively. Combining ARS and PAM significantly inhibited PTPase activity in both cell lines at lower concentrations of each drug. Pretreatment with N-acetyl-L-cysteine reversed ARS- and PAM-induced inhibition of PTPase activity. PTPase inhibition by ARS and/or PAM treatment in both DU-145 and PC-3 cells was associated with prolonged EGFR activation. These experiments demonstrate additive or synergistic cell killing by the ARS/PAM combination in DU-145 or PC-3 cells and suggest that enhanced antitumor activity may be related to alterations in receptor tyrosine kinase signaling that occur, in part, due to ROS-mediated PTPase inhibition.

Published
2020-03-01
How to Cite
Doroshow, J. H., & Gaur, S. (2020). Role of Reactive Oxygen Species in the Cytotoxicity of Arsenic Trioxide and Pamidronate for Human Prostate Cancer Cells. Reactive Oxygen Species, 9(26), 81–94. Retrieved from https://aimsci.com/ros/index.php/ros/article/view/260
Section
Original Research Articles