Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma.
Topoisomerase I inhibitors are effective anticancer therapies and have shown activity in hematologic malignancies. Here we show for the first time that SN38, the potent active metabolite of irinotecan, induces c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and caspase 8-mediated apoptosis in multiple myeloma (MM) cells. Proteasomal degradation of nuclear topoisomerase I has been proposed as a resistance mechanism in solid malignancies. SN38-induced proteasomal degradation of topoisomerase I was observed during SN38-mediated cytotoxicity against MM.1S myeloma cell line but occurred after c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage and failed to protect cells from apoptosis. Differential toxicity was observed against MM cells versus bone marrow stromal cells, and SN38 inhibited adhesion-induced up-regulation of MM cell proliferation when MM cells adhere to bone marrow stromal cells. In addition, SN38 directly inhibited constitutive and inducible interleukin 6 and vascular endothelial growth factor secretion by bone marrow stromal cells. Synergy was observed when SN38 was used in combination with doxorubicin, bortezomib, as well as poly(ADP-ribose) polymerase inhibitor NU1025 and Fas-activator CH11. These findings have clinical significance, because identification of downstream apoptotic signaling after topoisomerase I inhibition will both elucidate mechanisms of resistance and optimize future combination chemotherapy against MM.
Catley
Laurence
L
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. Laurence_Catley@dfci.harvard.edu
Tai
Yu-Tzu
YT
Shringarpure
Reshma
R
Burger
Renate
R
Son
Moni Thi
MT
Podar
Klaus
K
Tassone
Pierfrancesco
P
Chauhan
Dharminder
D
Hideshima
Teru
T
Denis
Louis
L
Richardson
Paul
P
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D000077146:Irinotecan; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
D001897:Boronic Acids; D004273:DNA, Neoplasm; D011719:Pyrazines; D019014:fas Receptor; D000069286:Bortezomib; D000077146:Irinotecan; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin