Anti-Cancer Activity of Nitrones and Observations on Mechanism of Action

Abstract

The nitrone compound PBN, α-phenyl-tert-butylnitrone, and closely related nitrones have anti-cancer activity in several experimental cancer models. The three experimental models most extensively studied include A) the rat choline deficiency liver cancer model, B) the rat C6 glioma model and C) the mouse APCMin/+ colon cancer model. The two PBN-nitrones mostly studied are PBN and a PBN derivative 2,4-disulfophenyl-tert-butylnitrone, referred as OKN-007. OKN-007 is a proprietary compound that has had extensive commercial development (designated as NXY-059) for another indication, acute ischemic stroke, and after extensive clinical studies was shown to lack efficacy for this indication but was shown to be very safe for human use. This compound administered orally in the rat glioma model has potent activity in treating fully formed gliomas. In this report observations made on the PBN-nitrones in experimental cancer models will be summarized. In addition the experimental results will be discussed in the general framework of the properties of the compounds with a view to try to understand the mechanistic basis of how the PBN-nitrones act as anti-cancer agents. Possible mechanisms related to the suppression of NO production, S-nitrosylation of critical proteins and inhibition of NF-κB activation are discussed.

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke

“…However, neuroprotection is still a choice, and oxidative stress, a suitable biological target. In this context, antioxidants such as N - t -butylphenylnitrone (PBN; Figure 1; Novelli et al, 1986) and NXY-059 (Figure 1; Dehouck et al, 2002), have attracted the interest of a number of laboratories, resulting in therapeutic candidates for cancer (Inoue et al, 2007; Floyd et al, 2008, 2010, 2011; Costa et al, 2015), neurodegenerative disorders (Floyd et al, 2000), hearing loss (Floyd et al, 2008) and stroke (Doggrell, 2006; Floyd et al, 2008). NXY-059 (Figure 1) (Kuroda et al, 1999) is a well-known free radical scavenger with good neuroprotective profile in rat models of transient and permanent focal ischemia, and stroke model in rodents, which has been launched several times in different program in advanced clinical studies, although with limited success (Macleod et al, 2008).…”

OKN-007 decreases free radical levels in a preclinical F98 rat glioma model

“…OKN-007 is a small molecule that can traverse the blood–brain barrier, and has anti-inflammatory, antioxidant, and proapoptotic properties [11–36]. Our group has also established that OKN-007 is an effective anticancer agent in rodent preclinical glioma models [8–10], and it is currently undergoing clinical trial assessment as a new investigational drug for recurrent adult glioblastomas.…”

Potential Implication of The Chemical Properties and Bioactivity of Nitrone Spin Traps for Therapeutics

“…[45,266], nitrone spin traps have been widely used as protective agents in several biological models, such as I/R injury to the heart [53,267,268], brain [269,270] and lung [271], stroke [47,55,272,273] neurodegenerative diseases [274-276], cancer [54,56,277,278], ageing [248,279], visual impairment [49,280] and loss of hearing function [281-283]. In two review articles published by Floyd et al .…”

“…In reviews by Floyd et al ., the anticancer role of PBN and PBN-derived compounds against hepatocellular carcinoma and glioma models had been elaborately discussed [54,55]. In this article, we have tried to focus on the recent developments of nitrone therapeutics in anticancer research and also highlight the mechanisms behind the anti-tumorigenic properties of nitrones, although the exact mode of nitrone action is still far from being understood.…”

“…Very recently, the cardio-protective functions of the cyclic nitrone, 5,5-dimethyl-1-pyrroline N -oxide ( DMPO ), against I/R injury have been reported [53]. The anticancer role of PBN and its derivatives against various types of cancer is also well documented [54,55]. The PBN-derived nitrones are reported to inhibit tumor growth and progression in hepatocellular carcinoma [56,57], brain cancer [58,59] and colon cancer [60] models.…”