Melittin suppresses growth and induces apoptosis of non-small-cell lung cancer cells via down-regulation of TGF-β-mediated ERK signal pathway

Abstract

The purpose of this study was to investigate the anti-cancer effect of melittin on growth, migration, invasion, and apoptosis of non-small-cell lung cancer (NSCLC) cells. This study also explored the potential anti-cancer mechanism of melittin in NSCLC cells. The results demonstrated that melittin suppressed growth, migration, and invasion, and induced apoptosis of NSCLC cells in vitro. Melittin increased pro-apoptotic caspase-3 and Apaf-1 gene expression. Melittin inhibited tumor growth factor (TGF)-b expression and phosphorylated ERK/total ERK (pERK/tERK) in NSCLC cells. However, TGF-b overexpression (pTGF-b) abolished melittin-decreased TGF-b expression and pERK/tERK in NSCLC cells. Treatment with melittin suppressed tumor growth and prolonged mouse survival during the 120-day observation in vivo. Treatment with melittin increased TUNEL-positive cells and decreased expression levels of TGF-b and ERK in tumor tissue compared to the control group. In conclusion, the findings of this study indicated that melittin inhibited growth, migration, and invasion, and induced apoptosis of NSCLC cells through down-regulation of TGF-b-mediated ERK signaling pathway, suggesting melittin may be a promising anti-cancer agent for NSCLC therapy.

Cytotoxic and Pro-Apoptotic Effects of a Sub-Toxic Concentration of Fluvastatin on OVCAR3 Ovarian Cancer Cells After its Optimized Formulation to Melittin Nano-Conjugates

“…Despite the significantly highest antineoplastic activity showed by FLV-MEL combination, the activity of MEL alone is also worth of mention. In fact, as showed in almost all in vitro cell experiments, the antineoplastic activity of MEL alone used at a sub-toxic concentration (IC10) was higher than that of the free drug (FLV-R) and is in accordance with several recent research studies (Sangboonruang et al, 2020;Yu et al, 2020) such as that carried out by Duffy et al showing the ability of MEL to suppress epidermal growth factor receptors 1 and 2 (EGFR and HER2) activation in the aggressive triple-negative and HER2-enriched breast cancer subtypes (Duffy et al, 2020). The present findings also confirm that the combination of this natural product with other antineoplastic drugs results in a more powerful anticancer activity.…”

A new therapeutic approach for bone metastasis in colorectal cancer: intratumoral melittin

“…The dose-response relationship demonstrates the effect with increasing dose levels, whose reached its maximum with 2 µM resulting in 80% inhibition ( Figure 1B ). This antiproliferative effect on colon cell agrees with literature [ 32 , 48 ]. The low tumor cell viability was also demonstrated on gastric [ 37 ], lung cancer [ 49 ], esophagus [ 34 ], lymphoma [ 29 ], leukemia [ 27 ], ovarian cancer [ 28 ], breast cancer [ 48 , 50 ], cervical cancer [ 43 ], skin cancers [ 20 , 31 ].…”

“…Due to its cytolytic effect, melittin has been tested in tumor cells, and has been shown to selectively induce cell death in cancer cells [27][28][29][30][31][32][33][34].…”

“…Nevertheless, one of the obstacles to melittin treatment is its high toxicity, which can induce severe complications such as hemolysis, coagulopathy, thrombocytopenia, rhabdomyolysis, and liver dysfunction by systemic administration [26,35,42]. Melittin conjugates and derivates have been described in most recent cancer studies [27][28][29][30][31][32][33][34]37,43] eradicating 100% of the tumor cells, including colon cancer cells, without adverse side effects [35,41]. Therefore, in the present study we propose a new approach based on melittin intrametastatic therapy to treat bone metastasis in CRC.…”

Stable Loading and Delivery of Melittin with Lipid-Coated Polymeric Nanoparticles for Effective Tumor Therapy with Negligible Systemic Toxicity

“…The activation of the apoptosis plays a critical role in melittin-mediated cancer treatments. ,,, Therefore, after confirming the melittin-stable loading and low hemolysis of the core–shell MpG@LPN, we investigated the apoptosis-inducing activity of PEG-MpG@LPN and RGD-MpG@LPN on the target tumor cells. One of the early events of apoptosis is the transfer of phosphatidylserine (PS), which resides on the cytoplasmic surface of the membrane, to the outer surface of cells .…”