Maduramicin triggers methuosis-like cell death in primary chicken myocardial cells

Maduramicin induces cardiotoxicity via Rac1 signaling‐independent methuosis in H9c2 cells

“…Maduramicin‐induced vacuoles acquired characteristics of LAMP‐1 can be explained by that partial macropinosomes may fuse with late endosomes or lysosomes and recruit LAMP‐1 to the membranes of macropinocytic vacuoles. Additionally, a specific inhibitor of vacuolar H + ‐ATPase, bafilomycin A1, completely rescued maduramicin‐induced cytoplasmic vacuolization and cell death, which was consistent with previous literatures showing that vacuolar H + ‐ATPase plays critical role in MIPP‐triggered cytoplasmic vacuolization in glioblastoma cells U251 (Overmeyer et al, 2011), maduramicin‐induced vacuolated primary chicken myocardial cells (Gao et al, 2020), and rabbit pulmonary artery smooth muscle cell vacuolization induced by procainamide (Morissette et al, 2004).…”

“…Transcriptome analysis indicates that maduramicin exerts its cardiotoxicity via multiple molecular pathways, including the release of pro‐inflammatory cytokines, apoptosis, the elevation of intracellular calcium level, and severely cytoplasmic vacuolization in primary chicken myocardial cells (Gao, Peng, et al, 2018). Our recent findings further demonstrate excessive cytoplasmic vacuolization as methuosis mediates cardiotoxicity of maduramicin in primary avian myocardial cells (Gao et al, 2020). Similarly, maduramicin also induces markedly cytoplasmic vacuoles in H9c2 cells (Chen, 2015); however, the relationship of cytotoxicity and maduramicin‐induced cytoplasmic vacuolization of H9c2 cells is largely unknown.…”

“…These include especially tumor cells such as A549 non‐small cell lung cancer cells (Brel et al, 2011), DU145 prostate cancer cells (Reyes‐Reyes et al, 2015), the gastric cancer cell line HGC‐27 (Cingolani et al, 2017), HeLa cells (Sun et al, 2017), colon cancer (SW‐480, DLD‐1, HT‐29, and HCT‐116) and nontumor (CoN) cells (Silva‐Pavez et al, 2019), leukemic U937 and NB4 cells (Yang et al, 2019), and HepG2 cells (D'Amore et al, 2020). In normal cells, excessive vacuole‐related cell death also has been reported in primary chicken myocardial cells and fibroblasts (Gao et al, 2020). Such growing evidences inspire that methuosis may act as an important non‐apoptotic cell death mechanism in a more extensive field.…”

“…This initiate work helps scientists recognize the significant importance of cellular vacuolization involved in cytotoxicity induced by pharmaceuticals or other toxic compounds. Recent evidences support the occurrence of methuosis in widespread cell types, including glioblastoma cells (Bhanot et al, 2010; Mbah et al, 2017), lung cancer cells (Brel et al, 2011), gastric cancer cells (Cingolani et al, 2017), pinewood nematode cells (Labudda et al, 2020; Rajasekharan et al, 2017), normal human epithelial cells (Dendo et al, 2018), breast cancer cells (Huang et al, 2018), colorectal cancer (CRC) cells (Silva‐Pavez et al, 2019), leukemia cells (Yang et al, 2019), malignant pleural mesothelioma cells (Sarkar et al, 2019), human hepatoma cells and in vivo zebrafish (D'Amore et al, 2020), and primary chicken myocardial cells shown in our recent report (Gao et al, 2020). These findings provide more mechanistic information of methuosis in many cell lines, especially in cancer cells.…”

Progress in the discovery and development of small molecule methuosis inducers

“…55 Gao et al proved that the non-apoptotic death of primary chicken embryo fibroblasts and chicken hepatoma cells (LMH) induced by maduramicin was methuosis. 56 Further exploration in rat cardiomyocytes (H9c2) revealed that maduramicin activated the Ras-Rac1 signal pathway at mRNA and protein levels leading to macropinocytosis imbalance, decreased intracellular ATP levels and increased LDH. 57…”