Induction of mitochondrial apoptotic pathway in triple negative breast carcinoma cells by methylglyoxal via generation of reactive oxygen species

Abstract

Triple negative breast cancer (TNBC) tends to form aggressive tumors associated with high mortality and morbidity which urge the need for development of new therapeutic strategies. Recently, the normal metabolite Methylglyoxal (MG) has been documented for its anti-proliferative activity against human breast cancer. However, the mode of action of MG against TNBC remains open to question. In our study, we investigated the anticancer activity of MG in MDA MB 231 and 4T1 TNBC cell lines and elucidated the underlying mechanisms. MG dose-dependently caused cell death, induced apoptosis, and generated ROS in both the TNBC cell lines. Furthermore, such effects were attenuated in presence of ROS scavenger N-Acetyl cysteine. MG triggered mitochondrial cytochrome c release in the cytosol and up-regulated Bax while down-regulated anti-apoptotic protein Bcl-2. Additionally, MG treatment down-regulated phospho-akt and inhibited the nuclear translocation of the p65 subunit of NF-κB. MG exhibited a tumor suppressive effect in BALB/c mouse 4T1 breast tumor model as well. The cytotoxic effect was studied using MTT assay. Apoptosis, ROS generation, and mitochondrial dysfunction was evaluated by flow cytometry as well as fluorescence microscopy. Western blot assay was performed to analyze proteins responsible for apoptosis. This study demonstrated MG as a potent anticancer agent against TNBC both in vitro and in vivo. The findings will furnish fresh insights into the treatment of this subgroup of breast cancer.

Glyoxalases in Urological Malignancies

“…MG is a crucial factor in the induction of oxidative stress and in the generation of reactive oxygen species (ROS) [ 40 , 44 , 45 , 46 , 47 , 48 ]. The major route by which MG generates ROS is by directly modifying proteins, e.g., mitochondrial membrane proteins [ 49 , 50 ], antioxidant enzymes [ 50 , 51 ], endothelial nitric oxide synthase [ 52 ] and NADPH oxidase [ 53 ]. Moreover, MG, mainly through MG-H1, which serves as a ligand for the receptor of AGEs (RAGE), is an important pro-inflammatory agent [ 40 , 54 , 55 , 56 ].…”

Activatable NIR-II Fluorescent Nanoprobe for Rapid Detection and Imaging of Methylglyoxal Facilitated by the Local Nonpolar Microenvironment

“…53 As a result, MGO concentrations tested by MG-SLNP in whole blood were slightly higher, which might be of great biological significance. Owing to abnormally high levels of MGO-induced oxidative stress, 54 bright green fluorescence derived from 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) was observed in mouse kidney slices of the db/db group (Figure 4H). Significant histological morphological changes in the kidney in Figure 4I show that the mesangial region widened and the mesangial matrix increased, which was mainly caused by hyperinsulinemia, verifying the establishment of T2D.…”

Targeted and Intrinsic Activity of HA-Functionalized PEI-Nanoceria as a Nano Reactor in Potential Triple-Negative Breast Cancer Treatment

“…As expected, the results showed a concentration-dependent increase in levels of Cyt c. This could result in the formation of apoptosome complex which can further activate caspase-3. 49 Moreover, in a majority of cancers and especially in TNBC, the level of antiapoptotic protein Bcl-2 is usually high, leading to inhibition of the permeability of mitochondria and is pivotal for the activation of apoptosis via mitochondria. 50−52 In our current research, we have demonstrated significant loss of MMP and hence as the next step, we also determined the level of Bcl-2.…”