s-allylcysteine and Lung-Neoplasms

The aim of this study is to explore the therapeutic potential of S-allylcysteine (SAC) organosulphur compound as a potent immune checkpoint inhibitor PD-L1.. Natural compounds have been showing tremendous anticancerous potential via suppressing the expression of genes involved in the development and progression of several carcinomas. This has further motivated us to explore the therapeutic potential of organosulphur compounds as potent immune checkpoint inhibitors.. Our study was designed to elucidate the potential of S-allylcysteine (SAC) as significant PD-L1 (immune checkpoint) inhibitor in human lung cancer A549 cancer cell line by using both the in vitro and in silico approaches.. Anticancerous effect of the SAC on lung cancer cells was determined by using the MTT cell viability. Apoptotic induction was confirmed by Hoechst staining, percent caspase-3 activity as well as gene expression analysis by real time PCR. Reactive Oxygen Species (ROS) was estimated by DCFDA method. Additionally, ligand-target protein interaction was analysed by molecular docking.. Cell growth and proliferation was significantly reduced in SAC treated A549 cells in a concentration and time.dependent manner. The effect of SAC on apoptotic induction was analyzed by enhanced nuclear condensation, increased percent caspase-3 activity as well as modulation of apoptotic genes. Furthermore, SAC treatment also resulted in reduced expression of PD-L1 and HIF-1α. Additionally, in silico analysis also supported the in vitro findings by showing efficient docking with PD-L1 immune checkpoint target.. Therefore, our results clearly suggested that SAC could serve as a novel chemotherapeutic candidate for the treatment of lung cancer by inhibiting immune checkpoint target PD-L1 in human lung cancer cells. Additionally, our study also explained a novel molecular mechanism of its antitumor activity.

Topics: Antineoplastic Agents; Apoptosis; B7-H1 Antigen; Cell Proliferation; Cell Survival; Cells, Cultured; Cysteine; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Reactive Oxygen Species

In this study, we investigated the putative cytotoxic effect elicited by the garlic-derived compound S-allylcysteine (SAC) in two human cancer cell lines (HCC827 and NCI-H1975) in order to develop an experimental approach to the therapeutic potential of this molecule for lung cancer. Cells were incubated for 24, 48 and 72 h in the presence of SAC (10 or 20 mM), which resulted in a concentration- and time-dependent decrease in cell viability and culture confluence in both cell lines. These effects were contrasted with - and validated through - those observed in an immortalized but nontumorigenic epithelial cell line from human bronchial epithelium (BEAS-2B, negative control) and an adenocarcinoma human alveolar basal epithelial cell line (A549, positive control). SAC (20 mM at 72 h) also increased the oxidative damage to lipids, augmented apoptosis, and decreased the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the nuclear factor kappa B (NF-κB) proteins in HCC827 and NCI-H1975 cells. Our results establish the efficacy of SAC in reducing malignant growth and proliferation of lung tumor cells. This effect is mediated by the induction of oxidative damage associated with the downregulation of Nrf2 and NF-κB and their corresponding signaling pathways.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cysteine; Dose-Response Relationship, Drug; Down-Regulation; Humans; Lipid Metabolism; Lung Neoplasms; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Signal Transduction; Time Factors

Lung cancer is one of the leading causes of cancer death in the world. Human non-small-cell lung carcinoma (NSCLC) accounts for almost 80% of lung cancer cases. Aberrant phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathways play important roles and have been widely observed in the development of NSCLC. Previous studies indicated that garlic extracts such as diallyl disulfide (DADS) and diallyl trisulfide (DATS) could inhibit the proliferation of several types of cancer in vitro. However, the inhibitory effects of S-allylcysteine (SAC) on the growth of NSCLC have not been demonstrated yet. Therefore, this study investigated whether consumption of SAC could prevent the growth of NSCLC in both in vitro and in vivo models. It was found that SAC significantly inhibited the proliferation of human NSCLC A-549 cells in vitro. Treatment of the NF-κB inhibitor, Bay-11-7082, could significantly inhibit the proliferation of NSCLC A-549 cells. The results demonstrated that SAC significantly suppressed the activation of mTOR, NF-κB, and cyclin D1 molecules in vitro. Furthermore, the results demonstrated that consumption of SAC significantly inhibited the growth of highly metastatic human NSCLC cells in tumor-bearing mice. Bioluminescence imaging and pathological and immunohistochemical (IHC) staining results also indicated that SAC could effectively suppress the growth and malignant progression of human NSCLC in vivo. The chemopreventive effects of SAC were associated with suppression of mTOR and NF-κB molecules in vivo. These results suggested that SAC could act as an effective agent against the malignant progression of human NSCLC in both in vitro and in vivo models.

Topics: Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cysteine; Female; Garlic; Growth Inhibitors; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Phosphatidylinositol 3-Kinases; Plant Extracts; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays