PM02734 (elisidepsin) induces caspase-independent cell death associated with features of autophagy, inhibition of the Akt/mTOR signaling pathway, and activation of death-associated protein kinase.

PM02734 (elisidepsin) is a synthetic marine-derived cyclic peptide of the kahalalide family currently in phase II clinical development. The mechanisms of cell death induced by PM02734 remain unknown. Human non-small-cell lung cancer (NSCLC) cell lines H322 and A549 were used to evaluate PM02734-induced cytotoxicity, apoptosis, and autophagy, as well as effects on cell death-related signaling pathways. PM02734 at clinically achievable concentrations (0.5-1 μmol/L) was cytotoxic to H322 and A549 cells but did not cause nuclear fragmentation, PARP cleavage, or caspase activation, suggesting that classical apoptosis is not its main mechanism of cell death. In contrast, PM02734-induced cell death was associated with several characteristics of autophagy, including an increase in acidic vesicular organelle content, levels of GFP-LC3-positive puncta, elevation of the levels of Atg-5/12 and LC3-II, and an associated compromise of the autophagic flux resulting in increased number of autophagosomes and/or autolysosomes. Cotreatment with 3-methyladenine (3-MA) and downregulation of Atg-5 gene expression by siRNA partially inhibited PM02734-induced cell death. PM02734 caused inhibition of Akt/mTOR signaling pathways and cotreatment with the Akt inhibitor wortmannin or with the mTOR inhibitor rapamycin led to a significant increase in PM02734-induced cell death. Furthermore, PM02734 caused the activation of death-associated protein kinase (DAPK) by dephosphorylation at Ser308, and downregulation of DAPK expression with siRNA caused also a partial but significant reduction of PM02734-induced cell death. In vivo, PM02734 significantly inhibited subcutaneous A549 tumor growth in nude mice (P < 0.05) in association with induction of autophagy. Our data indicate that PM02734 causes cell death by a complex mechanism that involves increased autophagosome content, due for the most part to impairment of autophagic flux, inhibition of the Akt/mTOR pathway, and activation of DAPK. This unique mechanism of action justifies the continued development of this agent for the treatment of NSCLC.

Ling YH ，Aracil M ，Zou Y ，Yuan Z ，Lu B ，Jimeno J ，Cuervo AM ，Perez-Soler R ... -  《-》

Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells.

Hwang KE ，Kim YS ，Jung JW ，Kwon SJ ，Park DS ，Cha BK ，Oh SH ，Yoon KH ，Jeong ET ，Kim HR ... -  《Oncotarget》

Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells.

Wang KF ，Yang H ，Jiang WQ ，Li S ，Cai YC ... -  《-》

Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models.

Ling YH ，Aracil M ，Jimeno J ，Perez-Soler R ，Zou Y ... -  《-》

Isogambogenic acid induces apoptosis-independent autophagic cell death in human non-small-cell lung carcinoma cells.

Yang J ，Zhou Y ，Cheng X ，Fan Y ，He S ，Li S ，Ye H ，Xie C ，Wu W ，Li C ，Pei H ，Li L ，Wei Z ，Peng A ，Wei Y ，Li W ，Chen L ... -  《Scientific Reports》