Antitumor activity of CDA-Ⅱ, a urinary preparation, on human multiple myeloma cell lines via the mitochondrial pathway.
Cell differentiation agent II (CDA‑II) is a DNA methyltransferase inhibitor isolated from healthy human urine. In the present study, the antitumor activity of CDA‑II on human multiple myeloma (MM) cell lines via the mitochondrial pathway was first revealed. The human MM cell lines were exposed to CDA‑II. Cytotoxicity, caspase activation, apoptosis and the effects on the mitochondrial pathway were assessed. CDA‑Ⅱ was capable of decreasing the depolarized mitochondrial membranes and activating caspase‑3 and ‑9 and poly (ADP‑ribose) polymerase in MM cells treated with CDA‑II. CDA‑II induced caspase‑dependent cell death accompanied by a significant decrease in X-linked inhibitor of apoptosis protein (XIAP), survivin and Mcl‑1 levels. The caspase‑3 inhibitor, Z‑DEVD‑FMK, inhibited CDA‑II‑induced apoptosis. CDA‑II potently increased the Bax levels, decreased the Bcl‑2/Bax ratio and decreased the expression of the downstream targets of NF‑κB. In conclusion, the results of the present study demonstrated that CDA‑II treatment leads to the inhibition of p65 nuclear localization and potently induces caspase‑dependent apoptosis in MM cells mediated through the mitochondrial pathway at low nanomolar concentrations. These results indicate that CDA‑II is a novel inhibitor of NF‑κB activity, with notable antimyeloma efficacy. This study provides a rationale for the clinical investigation of CDA‑Ⅱ in human MM.
Department of Hematology, Institute of Hematology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China.
Min
M
Yang
Department of Hematology, Institute of Hematology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China.
Jian
J
Huang
Department of Hematology, Institute of Hematology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China.
Qiu-Ling
QL
Ma
Department of Hematology, Institute of Hematology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China.
Gai-Xiang
GX
Xu
Department of Hematology, Institute of Hematology, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, P.R. China.
Jie
J
Jin
D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000652:urine; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000302:isolation & purification / Q000494:pharmacology* / Q000652:urine; D010648:Phenylacetates / Q000302:isolation & purification / Q000494:pharmacology* / Q000652:urine; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009842:Oligopeptides; D010455:Peptides; D010648:Phenylacetates; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051028:bcl-2-Associated X Protein; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C480340:cell differentiation agent II; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9