Autophagy inhibition sensitizes multiple myeloma cells to 17-dimethylaminoethylamino-17-demethoxygeldanamycin-induced apoptosis.
The Hsp90 inhibitor 17DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) is currently undergoing clinical trials as an antitumor drug. We show here that treatment of human multiple myeloma (MM) cells with 17DMAG induces mTOR inhibition and microtubule-associated protein light chain 3 (LC3) conversion (LC3-I to LC3-II), an indicator of autophagy. Interestingly, 17DMAG synergistically induces apoptosis through a mitochondria-operated pathway in the presence of the autophagy inhibitor 3-methyladenine (3-MA). Inhibition of autophagy by 3-MA facilitated caspase activation, cytochrome c release from mitochondria and poly (ADP-ribose) polymerase (PARP) cleavage in myeloma cells treated with 17DMAG. The potential use of Hsp90 and autophagy inhibitors combinations as a therapeutic tool in MM is further discussed in our work.
Palacios
Carmen
C
Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Sevilla, Spain. carmen.palacios@cabimer.es
Martín-Pérez
Rosa
R
López-Pérez
Ana Isabel
AI
Pandiella
Atanasio
A
López-Rivas
Abelardo
A
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D008928:Mitochondria / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C025946:3-methyladenine; D000225:Adenine