title: Novel X-linked inhibitor of apoptosis inhibiting compound as sensitizer for TRAIL-mediated apoptosis in chronic lymphocytic leukaemia with poor prognosis.
abstract: Given that aggressive DNA damaging chemotherapy shows suboptimal efficacy in chronic lymphocytic leukaemia (CLL), alternative therapeutic approaches are needed. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce tumour-specific apoptosis. However, apoptosis might be inhibited by elevated levels of X-linked inhibitor of apoptosis (XIAP). Use of XIAP-inhibiting compounds might sensitize primary CLL cells towards TRAIL-mediated apoptosis. A novel small molecule, compound A (CA), an inhibitor of XIAP, was used in combination with TRAIL to induce apoptosis in primary CLL cells (n = 48). XIAP was significantly more highly expressed in primary CLL cells (n = 28) compared to healthy B cells (n = 16) (P = 0·02). Our data obtained by specific knock-down of XIAP by siRNA identified XIAP as the key factor conferring resistance to TRAIL in CLL. Combined treatment with CA/TRAIL significantly increased apoptosis compared to untreated (P = 8·5 × 10⁻¹⁰), solely CA (P = 4·1 × 10⁻¹²) or TRAIL treated (P = 4·8 × 10⁻¹⁰) CLL cells. CA rendered 40 of 48 (83·3%) primary CLL samples susceptible to TRAIL-mediated apoptosis. In particular, cells derived from patients with poor prognosis CLL (ZAP-70(+) , IGHV unmutated, 17p-) were highly responsive to this drug combination. Our highly-effective XIAP inhibitor CA, in concert with TRAIL, shows potential for the treatment of CLL cases with poor prognosis and therefore warrants further clinical investigation.
authors.affiliation: Department I of Internal Medicine, University of Cologne, Germany. Lukas.frenzel@uk-koeln.de
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.forename: Michaela
authors.initials: M
authors.lastname: Patz
authors.forename: Christian P
authors.initials: CP
authors.lastname: Pallasch
authors.forename: Reinhild
authors.initials: R
authors.lastname: Brinker
authors.forename: Julia
authors.initials: J
authors.lastname: Claasen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schulz
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011379:Prognosis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human