Targeting Epidermal Growth Factor Receptor in Non-Small-Cell-Lung Cancer: Current State and Future Perspective.

BACKGROUND: Lung cancer is one of the leading cause of cancer death worldwide, the most common histological type of lung cancer is non-small cell lung cancer (NSCLC), whose occurrence and development is closely related to the mutation and amplification of epidermal growth factor receptors (EGFR). Currently , a series of targeted drugs were developed on the inhibition of EGFR such as epidermal growth factor receptortyrosine kinase inhibitor EGFR-TKI and monoclonal antibody (McAb). OBJECTIVE: We sought to summarizes the current drugs targeting Epidermal Growth Factor Receptor in nonsmall- cell-lung. METHODS: We conducted a comprehensive review of the development and application of EGFR-TKI and McAb which targeted EGFR in NSCLC and compared the mechanisms of PROTAC with the traditional inhibitors. RESULTS: The drugs targeted EGFR in NSCLC have been widely used in clinic practices. Compared to traditional chemotherapy, these drugs excel with their clear and specific targeting, better curative effects, and less toxic and side effects. However, the mechanism comes with some insurmountable weaknesses like serious toxic and other side effects, as well as proneness to producing drug resistance. CONCLUSION: The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, including EGFR. It also highlights the potential and challenges of PROTAC therapy regarding future combination therapeutic options in NSCLC treatment.

Corilagin induces apoptosis, autophagy and ROS generation in gastric cancer cells in vitro.

Corilagin, a unique component of the tannin family, has been identified in several medicinal plants. In previous literature, corilagin exhibited a marked anticancer property in a variety of human cancer cells. However, the biological effects of corilagin on gastric cancer and the mechanisms involved remain to be fully elucidated. In the present study, it was reported that corilagin induced inhibition of cell growth in SGC7901 and BGC823 cells in a concentration­dependent manner. It was found that corilagin exhibited less toxicity towards normal GES­1 cells. Furthermore, the study showed that corilagin induced the apoptosis of gastric cancer cells mainly via activating caspase­8, ­9, ­3 and poly ADP­ribose polymerase proteins. Simultaneously, it was verified that corilagin triggered autophagy in gastric cancer cells and the inhibition of autophagy improved the activity of corilagin on cell growth suppression. In addition, corilagin significantly increased intracellular reactive oxygen species production, which is important in inhibiting the growth of gastric cancer cells. Finally, it was shown that necroptosis cannot be induced by corilagin­incubation in SGC7901 and BGC823 cell lines. Consequently, these findings indicate that corilagin may be developed as a potential therapeutic drug for gastric cancer.

Corilagin inhibits breast cancer growth via reactive oxygen species-dependent apoptosis and autophagy.

Corilagin is a component of Phyllanthus urinaria extract and has been found of possessing anti-inflammatory, anti-oxidative, and anti-tumour properties in clinic treatments. However, the underlying mechanisms in anti-cancer particularly of its induction of cell death in human breast cancer remain undefined. Our research found that corilagin-induced apoptotic and autophagic cell death depending on reactive oxygen species (ROS) in human breast cancer cell, and it occurred in human breast cancer cell (MCF-7) only comparing with normal cells. The expression of procaspase-8, procaspase-3, PARP, Bcl-2 and procaspase-9 was down-regulated while caspase-8, cleaved PARP, caspase-9 and Bax were up-regulated after corilagin treatment, indicating apoptosis mediated by extrinsic and mitochondrial pathways occurred in MCF-7 cell. Meanwhile, autophagy mediated by suppressing Akt/mTOR/p70S6K pathway was detected with an increase in autophagic vacuoles and LC3-II conversion. More significantly, inhibition of autophagy by chloroquine diphosphate salt (CQ) remarkably enhanced apoptosis, while the caspase inhibitor z-VAD-fmk failed in affecting autophagy, suggesting that corilagin-induced autophagy functioned as a survival mechanism in MCF-7 cells. In addition, corilagin induced intracellular reactive oxygen species (ROS) generation, when reduced by ROS scavenger NAC, apoptosis and autophagy were both down-regulated. Nevertheless, in SK-BR3 cell which expressed RIP3, necroptosis inhibitor Nec-1 could not alleviate cell death induced by corilagin, indicating necroptosis was not triggered. Subcutaneous tumour growth in nude mice was attenuated by corilagin, consisting with the results in vitro. These results imply that corilagin inhibits cancer cell proliferation through inducing apoptosis and autophagy which regulated by ROS release.

Mesenchymal stem cells in inflammatory microenvironment potently promote metastatic growth of cholangiocarcinoma via activating Akt/NF-κB signaling by paracrine CCL5.

Our previous work has demonstrated that mesenchymal stem cells (MSCs) could induce metastatic growth of the inflammation-related cholangiocarcinoma (CCA). However, the functional mechanism of MSCs on CCA progression in the early inflammatory microenvironment remained undetermined. Here, we showed that TNF-α and IFN-γ-induced inflammatory microenvironment stimulated the expression of TNF-α, CCL5, IL-6, IDO, and activated the NF-κB signaling with p65 nuclear translocation in MSCs cells. CCA cell lines QBC939 and Mz-chA-1 exposed to the conditioned medium of MSCs after being stimulated by TNF-α and IFN-γ (TI-CM) exhibited enhanced mobility. Moreover, MSCs pre-stimulated by both inflammatory cytokines (TI-MSCs) increased tumor metastasis in vivo. The conditioned medium of TI-MSCs stimulated the transcription of snail, slug, ZEB1 and ZEB2. Next, the expression of CCL5 of TI-MSCs was verified by ELISA, which indicated that MSCs contributed to CCA migration and metastasis in a paracrine fashion. CCA cells treated with TI-CM up-regulated CCA chemokine receptors, especially CCR5; CCL5 neutralizing antibody or CCR5 inhibitor Maraviroc inhibited the effects of MSCs on CCA cells migration. We also found that Akt/NF-κB signaling was activated by CCL5/CCR5 axis, which increased the expression of MMP2, MMP9. Together, these findings suggest that MSCs in tumor inflammatory microenvironment are elicited of CCL5, which activate AKT/NF-κB signaling and lead to metastatic growth of CCA cells.

Involvement of Wnt/ß-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma.

Mesenchymal stem cells (MSCs) are multi-potent progenitor cells with ability to differentiate into multiple lineages, including bone, cartilage, fat, and muscles. Recent research indicates that MSCs can be efficiently recruited to tumor sites, modulating tumor growth and metastasis. However, the underlying molecular mechanisms are not fully understood. Here, we first demonstrated that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), when mixed with human cholangiocarcinoma cell lines QBC939 in a xenograft tumor model, significantly increased the cancer cells proliferation and metastatic potency. MSCs and their conditioned media (MSC-CM) could improve the drug resistance of tumor when the compound K (CK) as an anti-cancer drug, a major intestinal bacterial metabolite of panaxoside, was administered to xenograft tumor mice. Furthermore, MSCs greatly increased the colony formation and invasion of cholangiocarcinoma cells QBC939 and Mz-ChA-1. Immunochemistry studies of cholangiocarcinoma tissue chips and transplantation tumor from nude mice showed that the expression of ß-catenin was important for cholangiocarcinoma development. We further demonstrated that MSCs and MSCs-CM could promote proliferation and migration of cholangiocarcinoma cells through targeting the Wnt/ß-catenin signaling pathway. hUC-MSCs or MSCs-CM stimulated Wnt activity by promoting the nuclear translocation of ß-catenin, and up-regulated Wnt target genes MMPs family, cyclin D1 and c-Myc. Together, our studies highlight a critical role for MSCs on cancer metastasis and indicate MSCs promote metastatic growth and chemoresistance of cholangiocarcinoma cells via activation of Wnt/ß-catenin signaling.