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Prostate. 2018 Feb;78(2):140-151. doi: 10.1002/pros.23455. Epub 2017 Nov 6.

The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress.

Author information

1
Department of Biochemistry, LIA-BPPN, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
2
Department of Urology, The James Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Department of Biophysics and Biometry, Laboratory of Cancer Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.
4
IPPN, Laboratory of Chemistry Bioorganic, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Abstract

BACKGROUND:

The targeted induction of reactive oxygen species (ROS) is a developing mechanism for cancer therapy. LQB-118 is a pterocarpanquinone and ROS-inducing agent with proven antineoplastic activity. Here, LQB-118 efficacy and mechanism of activity, were examined in Prostate Cancer (PCa) cell and tumor models.

METHODS:

PC3, LNCaP, and LAPC4 PCa cells were applied. Dicoumarol treatment was used to inhibit quinone reductase activity. N-acetylcysteine (NAC) was applied as a ROS scavenger. ROS production was quantified by H2 DCFDA flow cytometry. LQB-118 treated cells were evaluated for changes in lipid peroxidation, viability, and apoptosis. Treatment-induced gene expression was measured by RT-qPCR and Western Blot. SOD1 knockdown was achieved with siRNA or miRNA mimic transfection. MicroRNA specificity was determined by 3'UTR reporter assay. Oral LQB-118 treatment (10 mg/kg/day) efficacy was determined in athymic male nude mice bearing subcutaneous PC3 xenograft tumors.

RESULTS:

LQB-118 treatment triggered PCa cell death and apoptosis. Therapeutic activity was at least partially dependent upon quinone reduction and ROS generation. LQB-118 treatment caused an increase in cellular ROS and lipid peroxidation. Treated cells exhibited elevated levels of NQO1, Nrf2, and SOD1. The miRNAs miR-206, miR-1, and miR-101 targeted and reduced SOD1 expression. The knockdown of SOD1, by siRNA or miRNA, enhanced LQB-118 cytotoxicity. Orally administered LQB-118 treatment significantly reduced the growth of established PCa xenograft tumors.

CONCLUSION:

LQB-118 is a developing and orally active pterocarpanquinone agent that effectively kills PCa cells through quinone reduction and ROS generation. The inhibition SOD1 expression enhances LQB-118 activity, presumably by impairing the cellular antioxidant response.

KEYWORDS:

NQO1; Nrf2; Pterocarpanquinone; SOD1; microRNA; siRNA

PMID:
29105806
PMCID:
PMC5726914
DOI:
10.1002/pros.23455
[Indexed for MEDLINE]
Free PMC Article

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