Effect of autophagy on multiple myeloma cell viability.
Because accumulation of potentially toxic malfolded protein may be extensive in immunoglobulin-producing multiple myeloma (MM) cells, we investigated the phenomenon of autophagy in myeloma, a physiologic process that can protect against malfolded protein under some circumstances. Autophagy in MM cell lines that express and secrete immunoglobulin and primary specimens was significantly increased by treatment with the endoplasmic reticulum stress-inducing agent thapsigargin, the mammalian target of rapamycin inhibitor rapamycin, and the proteasome inhibitor bortezomib. Inhibition of basal autophagy in these cell lines and primary cells by use of the inhibitors 3-methyladenine and chloroquine resulted in a cytotoxic effect that was associated with enhanced apoptosis. Use of small interfering RNA to knock down expression of beclin-1, a key protein required for autophagy, also inhibited viable recovery of MM cells. Because the data suggested that autophagy protected MM cell viability, we predicted that autophagy inhibitors would synergize with bortezomib for enhanced antimyeloma effects. However, the combination of these drugs resulted in an antagonistic response. In contrast, the autophagy inhibitor 3-methyladenine did synergize with thapsigargin for an enhanced cytotoxic response. These data suggest that autophagy inhibitors have therapeutic potential in myeloma but caution against combining such drugs with bortezomib.
Hoang
Bao
B
Department of Medicine, Division of Hematology-Oncology of the Greater Los Angeles Veterans Affairs Healthcare Center, University of California at Los Angeles Medical School, Los Angeles, CA 90073, USA.
Benavides
Angelica
A
Shi
Yijiang
Y
Frost
Patrick
P
Lichtenstein
Alan
A
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000935:Antifungal Agents; D000962:Antimalarials; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; C025946:3-methyladenine; D019284:Thapsigargin; D000069286:Bortezomib; D002738:Chloroquine; D000225:Adenine; D020123:Sirolimus