N-Acetyl-l-cysteine Enhances the Effect of Selenium Nanoparticles on Cancer Cytotoxicity by Increasing the Production of Selenium-Induced Reactive Oxygen Species

Abstract

Peritoneal carcinomatosis (PC) has an extremely poor prognosis, which leads to a significantly decreased overall survival in patients with peritoneal implantation of cancer cells. Administration of sodium selenite by intraperitoneal injection is highly effective in inhibiting PC. Our previous study found that selenium nanoparticles (SeNPs) have higher redox activity and safety than sodium selenite. In the present study, we examined the therapeutic effect of SeNPs on PC and elucidated the potential mechanism. Our results revealed that intraperitoneal delivery of SeNPs to cancer cells in the peritoneal cavity of mice at a tolerable dose was beneficial for prolonging the survival time of mice, even better than the optimal dose of cisplatin. The underlying mechanism involved in SeNP-induced reactive oxygen species (ROS) production caused protein degradation and apoptotic response in cancer cells. Interestingly, N-acetyl-L-cysteine (NAC), recognized as a ROS scavenger, without reducing the efficacy of SeNPs, enhanced ROS production and cytotoxicity. The effect of NAC was associated with the following mechanisms: (1) the thiol groups in NAC can increase the biosynthesis of endogenous glutathione (GSH), thus increasing the production of SeNP-induced ROS and cytotoxicity and (2) redox cycling of SeNPs was directly driven by thiol groups in NAC to produce ROS. Moreover, NAC, without increasing the systematic toxicity of SeNPs, decreased SeNP-induced lethality in healthy mice. Overall, we demonstrated that SeNPs exert a potential cytotoxicity effect by inducing ROS production in cancer cells; NAC effectively heightens the property of SeNPs in vitro and in vivo.

Selenium Nanoparticles for Biomedical Applications: From Development and Characterization to Therapeutics

“…While SeNPs administration at the dosages of 5 or 6 mg kg −1 led to 25 or 50% survival in healthy animals, coadministration with NAC (250 mg kg −1 ) enhanced the survival to 87.5 or 100%, indicating that NAC reduced SeNPs lethality as well. [ 236 ] Bidkar et al showed that SeNPs stabilized with pluronic F‐127 and loaded with paclitaxel (PTX) inhibit the growth of A549, HeLa, HT29 and MCF7 cells with IC 50 values of 13.8 × 10 −6 , 8.7 × 10 −6 , 4.8 × 10 −6 , and 5.4 × 10 −6 m , respectively, which represents an improved antitumor activity when compared with unloaded SeNPs. SeNPs@PTX induced apoptosis by two main mechanisms.…”

Biogenic Selenium Nanoparticles in Biomedical Sciences: Properties, Current Trends, Novel Opportunities and Emerging Challenges in Theranostic Nanomedicine

“…This process leads to a rapid and selective hyper-accumulation of SeNPs in cancer cells, which causes catastrophic oxidative stress and cell death. This underlying concept relies on two observations: firstly, the presence of higher basal levels of ROS in cancer cells compared to normal cells; secondly, cancer cells possess lower tolerance to increased levels of ROS than normal cells [ 288 , 292 , 293 ]. The process of ROS production, mediated by SeNPs, is illustrated in Figure 5 .…”

“…The intraperitoneal delivery of SeNPs has emerged as an effective and safe approach in preventing the growth of cancer cells in the peritoneal cavity without remarkable liver toxicity symptoms [ 294 ]. For example, Zhao et al demonstrated that SeNPs delivered to hepatocarcinoma-22 cells in the peritoneal cavity of mice induce ROS production and cause protein degradation and apoptotic response [ 293 ]. This study showed that GSH can stimulate a dose-dependent redox biotransformation of SeNPs to generate ROS in a pure enzymatic system, especially given that GSH is the cell’s most abundant thiol-containing small molecule.…”

Selenium as an important factor in various disease states - a review

“…The way selenium acts on cancer cells involves the production of ROS and modification of the thiol group. This procedure brings about effects that disrupt transcription and changes related to the endoplasmic reticulum (Zhao et al, 2020[ 86 ]; Razaghi et al, 2021[ 59 ]). It is worth noting that selenium may be helpful in the treatment of advanced forms of cancer through its cytotoxic effect that damages cancer cells.…”