Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells

Cell Death Dis. 2018 Oct 15;9(11):1048. doi: 10.1038/s41419-018-1006-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma, Bronchiolo-Alveolar / drug therapy*
  • Adenocarcinoma, Bronchiolo-Alveolar / genetics
  • Adenocarcinoma, Bronchiolo-Alveolar / metabolism
  • Adenocarcinoma, Bronchiolo-Alveolar / pathology
  • Animals
  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Artemisinins / chemical synthesis
  • Artemisinins / pharmacology*
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Gene Expression Regulation, Neoplastic*
  • HMGB1 Protein / antagonists & inhibitors
  • HMGB1 Protein / genetics*
  • HMGB1 Protein / metabolism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Tumor Burden / drug effects
  • Vacuoles / drug effects
  • Vacuoles / metabolism
  • Vacuoles / ultrastructure
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Phytogenic
  • Artemisinins
  • HMGB1 Protein
  • HMGB1 protein, human
  • MAP1LC3A protein, human
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • artenimol
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 8