Abstract
Dihydroartemisinin (DHA) and its analogs are reported to possess selective anticancer activity. Here, we reported a novel DHA derivative DHA-37 that exhibited more potent anticancer activity on the cells tested. Distinct from DHA-induced apoptosis, DHA-37 triggered excessive autophagic cell death, and became the main contributor to DHA-37-induced A549 cell death. Incubation of the cells with DHA-37 but not DHA produced increased dots distribution of GFP-LC3 and expression ratio of LC3-II/LC3-I, and enhanced the formation of autophagic vacuoles as revealed by TEM. Treatment with the autophagy inhibitor 3-MA, LY294002, or chloroquine could reverse DHA-37-induced cell death. In addition, DHA-37-induced cell death was associated significantly with the increased expression of HMGB1, and knockdown of HMGB1 could reverse DHA-37-induced cell death. More importantly, the elevated HMGB1 expression induced autophagy through the activation of the MAPK signal but not PI3K-AKT–mTOR pathway. In addition, DHA-37 also showed a wonderful performance in A549 xenograft mice model. These findings suggest that HMGB1 as a target candidate for apoptosis-resistant cancer treatment and artemisinin-based drugs could be used in inducing autophagic cell death.
Highlights
Non-small-cell lung cancer (NSCLC) accounts for85–90% of lung cancer deaths due to relatively insensitive or development of resistance to chemotherapy[1,2]
Our result showed that DHA-37 could effectively inhibit human lung carcinoma A549 cell, human stomach cancer SGC-7901 cell, human cervical carcinoma Hela cell, human breast cancer MDA-MB-231 and MCF-7 cells at the concentration of 10 μM in 48 h
The results shown are representative of three experiments. e, f A549 cells with or without 10 μM DHA-37 treatment for indicated times were analyzed by western blot for phosphorylated and total ERK (e) and p38 expression (f). g A549 cells pretreated with 10 μM PD98059 and/or DHA-37 for 24 h were analyzed by western blot using indicated antibodies. h A549 cells were treated with PD98059 and/or 10 μM DHA-37 for 48 h
Summary
Non-small-cell lung cancer (NSCLC) accounts for85–90% of lung cancer deaths due to relatively insensitive or development of resistance to chemotherapy[1,2]. Many attempts have been made to develop novel chemotherapies either by exploring the anticancer ability of novel compounds or by assessing drugs conventionally used in other clinical diseases. Traditional Chinese medicine (TCM) have been known to be effective against a range of diseases and considered to be a natural source of novel and potent anticancer drugs with minimal side effects in clinical. It has been found that artemisinin and its derives have potent anticancer activity[5,6]. Among these derives, artesunate and DHA are considered to be the most active compounds and subsequently many researchers have been focused on developing novel compounds with enhanced activity, increased selectivity, and low toxicity in vitro. The molecular mechanism of DHA-37-induced cell death needs to be further studied
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