Proteasome inhibitor MG132 enhances the sensitivity of human OSCC cells to cisplatin via a ROS/DNA damage/p53 axis

Abstract

Cis-diamine-dichloroplatinum II (cisplatin, CDDP) is a key chemotherapeutic regimen in the treatment of oral squamous cell carcinoma (OSCC). However, the therapeutic efficacy of cisplatin in OSCC may be hampered by chemoresistance. Therefore, the development of novel combination therapy strategies to overcome the limitations of CDDP is of great importance. The proteasome inhibitor MG132 exhibits anti-cancer properties against various types of cancer. However, our knowledge of its anti-cancer effects in combination with CDDP in OSCC cells remains limited. In the current study, the synergetic effects of MG132 and CDDP were evaluated in the human CAL27 OSCC cell line. CAL27 cells were treated with CDDP alone or in combination with MG132. The results showed that MG132 significantly reduced cell viability in a dose-dependent manner. Additionally, cell viability was significantly reduced in CAL27 cells treated with 0.2 µM MG132 and 2 µM CDDP compared with cells treated with MG132 or CDDP alone. In addition, MG132 significantly enhanced the CDDP-induced generation of intracellular reactive oxygen species and DNA damage in OSCC cells. Furthermore, treatment with CDDP or MG132 alone notably inhibited colony formation and proliferation of OSCC cells. However, co-treatment of OSCC cells with MG132 and CDDP further hampered colony formation and proliferation compared with cells treated with either MG132 or CDDP alone. Finally, in cells co-treated with MG132 and CDDP, the expression of p53 was markedly elevated and the p53-mediated apoptotic pathway was further activated compared with cells treated with MG132 or CDDP alone, as shown by the enhanced cell apoptosis, Bax upregulation, and Bcl-2 downregulation.Overall, the results of the current study support the synergistic anti-cancer effects of a combination of MG132 and CDDP against OSCC, thus suggesting that the combination of MG132 and CDDP may be a promising therapeutic strategy for the management of OSCC.

The Synergistic Effect of Reduced Graphene Oxide and Proteasome Inhibitor in the Induction of Apoptosis through Oxidative Stress in Breast Cancer Cell Lines

“…The induction of apoptosis was observed simultaneously with the intensification of oxidative stress in HepG2 cells induced through GO/rGO [7]. Similar results were presented by Zheng et al Researchers have shown that MG-132 induces ROS synthesis and at the same time leads to an increase in the level of Bax and p53 proteins and a decrease in the level of Bcl-2 protein in OSCC cells [10]. In our previous study, we indicated that rGO could induce apoptosis through the oxidative stress pathway in ZR-75-1 and MDA-MB-231 cell lines.…”

“…In contrast, the proteasome inhibitor MG-132 can effectively inhibit the proteolytic activity of the 26S proteasome complex and induces strong oxidative stress leading to cytotoxicity. It has been shown that the sharp edges of rGO can mechanically damage cell membranes, leading to the release of LDH from cells [10,11]. The ROS cause lipid pre-oxidation, and thus, large amounts of LDH are released into the culture medium.…”

“…According to the literature data, rGO and MG-132 may change human cellular metabolism by influencing oxidative stress processes. The main factors that induce oxidative stress in breast cancer cells incubated in the presence of MG-132 and rGO are reactive oxygen species (ROS) [10,11]. ROS play a pivotal role in various biological processes.…”

“…In our previous work, we demonstrated the effectiveness of rGO as a pro-apoptotic agent [9]. In turn, literature data indicate the anticancer effect of a proteasome inhibitor (MG-132) [10]. An innovative, previously undemonstrated aspect of this work is the combination of these two effective factors, which can not only enhance the pro-apoptotic effect, but also possibly reduce the level of toxicity of these compounds in the body, while simultaneously demonstrating anticancer activity.…”

Combination Therapy as a Promising Way to Fight Oral Cancer

“…In OSCC, different proteasome inhibitors in combination with Cisplatin enhanced apoptosis through dissociation of the E-cadherin/β-catenin complex essential for cell adhesion [ 60 ]. Recently, proteasome inhibitors were shown to sensitize OSCC to Cisplatin through the ROS/DNA damage/p53 axis [ 61 ]. Gimeracil is known to enhance the antitumor effects of 5-FU and improve radiotherapy efficacy by inhibiting DNA repair pathways.…”