Mesopore-encaged active MnOx in nano-silica selectively suppresses lung cancer cells by inducing autophagy.

Autophagy induced by nanomaterials is one of the intracellular catabolic pathways that degrade and recycle the biomacromolecules and damaged organelles in cells and has emerged as a very promising pharmacological target critical to future drug development and anti-cancer therapy. Herein, we developed mesopore-encaged highly-dispersed active cluster-like MnOx in nanosilica entitled MnO-MS, with a size of around 130 nm. Our studies show that MnO-MS could not only obviously induce autophagy in both stable GFP-LC3 HeLa cells and GFP-LC3-mCherry HeLa cells but also could selectively inhibit lung cancer A549 cell growth at 11.19 µg mL-1 (IC50) while exhibiting little cytotoxicity in normal cells. Encouraged by these interesting results, a further mechanistic study reveals that reactive oxygen species (ROS) were excited by the active MnOx in nanosilica, leading to the disruption of mitochondrial membrane potential (MMP), enhancement of ATG5A/ATG16L/ATG4B/Beclin1, and finally, inhibition of the mTOR signaling pathways. Collectively, these findings indicate that MnO-MS-induced cell death via autophagy pathways in cancer cells. Furthermore, MnO-MS significantly inhibited tumor growth with minimal side effects in vivo, and it is envisioned that MnO-MS can be further developed as a potential autophagy inducer for the treatment of lung cancers.

Reaction pathways and free energy profiles for spontaneous hydrolysis of urea and tetramethylurea: unexpected substituent effects.

It has been difficult to directly measure the spontaneous hydrolysis rate of urea and, thus, 1,1,3,3-tetramethylurea (Me4U) was used as a model to determine the "experimental" rate constant for urea hydrolysis. The use of Me4U was based on an assumption that the rate of urea hydrolysis should be 2.8 times that of Me4U hydrolysis because the rate of acetamide hydrolysis is 2.8 times that of N,N-dimethyl-acetamide hydrolysis. The present first-principles electronic-structure calculations on the competing non-enzymatic hydrolysis pathways have demonstrated that the dominant pathway is the neutral hydrolysis via the CN addition for both urea (when pH < ~11.6) and Me4U (regardless of pH), unlike the non-enzymatic hydrolysis of amides where alkaline hydrolysis is dominant. Based on the computational data, the substituent shift of the free energy barrier calculated for the neutral hydrolysis is remarkably different from that for the alkaline hydrolysis, and the rate constant for the urea hydrolysis should be ~1.3 × 10(9)-fold lower than that (4.2 × 10(-12) s(-1)) measured for the Me4U hydrolysis. As a result, the rate enhancement and catalytic proficiency of urease should be 1.2 × 10(25) and 3 × 10(27) M(-1), respectively, suggesting that urease surpasses proteases and all other enzymes in its power to enhance the rate of reaction. All of the computational results are consistent with available experimental data for Me4U, suggesting that the computational prediction for urea is reliable.