Apocynin, an NADPH oxidase inhibitor, suppresses rat prostate carcinogenesis

Abstract

Recent evidence suggests that oxidative stress contributes to the pathogenesis of prostate cancer. The present study focused on the effect of apocynin, an inhibitor of NADPH oxidase, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model. There were no toxic effects with apocynin treatment. The percentages and numbers of carcinomas in both the ventral and lateral prostate were significantly reduced by apocynin treatment, with dose dependence. Reduction of reactive oxygen species by apocynin was confirmed by immunohistochemistry of 8-OHdG and dihydroethidium staining. Positivity of Ki67 was significantly reduced by apocynin treatment, and downregulation of clusterin expression, as well as inactivation of the MEK-ERK1 ⁄ 2 pathway, was a feature of the apocynin treated groups. In human prostate cancer cell line LNCaP, apocynin also inhibited reactive oxygen species production and blocked cell growth by inducing G0 ⁄ G1 arrest with downregulation of clusterin and cyclin D1. These data suggest that apocynin possesses chemopreventive potential against prostate cancer. (Cancer Sci 2013; 104: 1711-1717 P rostate cancer is the second most frequently diagnosed cancer in men in the world, with particularly high incidences in Oceania, Europe and North America. In Japan, incident and mortality rates for prostate cancer are relatively low are but increasing.(1,2) There are potentially curative options, such as radical prostatectomy or radiotherapy, but once the disease is metastatic, the outlook is poor. Therefore, research into chemoprevention of prostate cancer is critical.Reactive oxygen species (ROS) can be important factors for carcinogenesis and tumor progression, not only inducing DNA damage but also producing cellular alterations, such as upregulation of MAPK and protein kinase C. (3,4) Recently, oxidative stress has been reported to contribute to cancer and progression in the prostate.(5,6) Therefore, we have focused on inhibition of ROS production as an anti-carcinogenic approach. ROS is produced by mitochondria, peroxisomes, cytochrome P-450 and other cellular elements as a byproduct, and is generated by NADPH oxidase, which is also implicated in a variety of signaling events, including cell growth, cell survival and cell death.(7) Apocynin, which belongs to the methoxysubstituted catechol family, inhibits NADPH oxidase activity by blocking the formation of NADPH oxidase complex (8) and is commonly used as a standard NOX inhibitor for research purposes.(7) In addition, apocynin can be converted by peroxidase-mediated oxidation to a dimer, which has been shown to be a more efficient inhibitor than apocynin itself.(9) We previously presented evidence that apocynin reduced oxidative stress induced by arsenite treatment of rat urothelium in vivo. (10) In the present study we focus on NADPH oxidase and test whether its inhibitor, apocynin, is able to suppress prostate carcinogenesis in the transgenic rat for adenocarcinoma of prostate (TRAP) model, which was generated in our labo...

Suppressive effects of the NADPH oxidase inhibitor apocynin on intestinal tumorigenesis in obese KK‐Ay and Apc mutant Min mice

“…It has been reported that Nox1 knockdown induces G 0 /G 1 arrest in a human colon cell line, HT29, whereas the same knockdown treatment in Caco2 cells strongly induces apoptosis . In addition, apocynin also blocks cell growth by inducing G 0 /G 1 arrest and downregulating cyclin D1 in a human prostate cancer cell line, LNCaP . We obtained similar results, showing that apocynin suppressed c‐Myc and cyclin D1 mRNA levels and reduced the ratio of PCNA‐positive epithelial cells in the intestinal polyp sections of Min mice.…”

Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis

“…Previous studies have shown that mitogen-activated protein kinases (MAPKs) became inactivated after the treatment of cancer cells with chemopreventive agents, such as angiotensin II receptor blocker, purple corn color or apocynin [16,17,18]. To elucidate the mechanisms of anti-carcinogenesis by PGZ, we therefore investigated the activation of p38 MAPK and ERK1/2 in prostate tissues of TRAP rats.…”

“…Neoplastic lesions in the prostate gland of TRAP rats were evaluated as previously described [17,18,30]. Briefly, neoplastic lesions were classified into three types: LG-PIN, HG-PIN and adenocarcinoma.…”

Critical Dietary Factors in Cancer Chemoprevention

“…The ratio and numbers of carcinomas in prostates were significantly reduced by apocynin treatment, with dose dependence (Suzuki et al 2013a). The ratio and numbers of carcinomas in prostates were significantly reduced by apocynin treatment, with dose dependence (Suzuki et al 2013a).…”