The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress.
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.
['Martino|Thiago|T|', 'Kudrolli|Tarana A|TA|', 'Kumar|Binod|B|', 'Salviano|Isis|I|', 'Mencalha|André|A|', 'Coelho|Marsen Garcia P|MGP|', 'Justo|Graça|G|', 'Costa|Paulo R Ribeiro|PRR|', 'Sabino|Kátia C Carvalho|KCC|http://orcid.org/0000-0002-1249-0209', 'Lupold|Shawn E|SE|']
D000284:Administration, Oral D000818:Animals D000970:Antineoplastic Agents D045744:Cell Line, Tumor D004195:Disease Models, Animal D006801:Humans D008297:Male D051379:Mice D008819:Mice, Nude D009285:Naphthoquinones D011467:Prostate D011471:Prostatic Neoplasms D036343:Pterocarpans D017382:Reactive Oxygen Species D016896:Treatment Outcome
Pterocarpanquinone SOD1 siRNA microRNA NQO1 Nrf2