Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome.
Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits beta5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138+ tumor cells. Although specific inhibition of either LMP7 or beta5 alone was insufficient to produce an antitumor response, inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells. However, selective inhibition of both beta5 and LMP7 was sufficient to induce an antitumor effect in MM, non-Hodgkin lymphoma, and leukemia cells while minimizing the toxicity toward nontransformed cells. In MM tumor cells, CT-L inhibition alone was sufficient to induce proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2alpha suppression. These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors.
Parlati
Francesco
F
Department of Research, Proteolix Inc, South San Francisco, CA 94080, USA. francescoparlati@gmail.com
Lee
Susan J
SJ
Aujay
Monette
M
Suzuki
Erika
E
Levitsky
Konstantin
K
Lorens
James B
JB
Micklem
David R
DR
Ruurs
Paulina
P
Sylvain
Catherine
C
Lu
Yan
Y
Shenk
Kevin D
KD
Bennett
Mark K
MK
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004790:Enzyme Induction / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D009842:Oligopeptides; C498702:PMAIP1 protein, human; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C524865:carfilzomib; D002918:Chymotrypsin; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D046988:Proteasome Endopeptidase Complex