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Antitumor activity of CDA-Ⅱ, a urinary preparation, on human multiple myeloma cell lines via the mitochondrial pathway.
- Source :
-
Molecular medicine reports [Mol Med Rep] 2014 Mar; Vol. 9 (3), pp. 1025-31. Date of Electronic Publication: 2014 Jan 22. - Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Antineoplastic Agents isolation & purification
Antineoplastic Agents urine
Caspase 3 chemistry
Caspase 3 metabolism
Caspase 9 metabolism
Caspase Inhibitors pharmacology
Cell Line, Tumor
Humans
Interleukin-6 metabolism
Membrane Potential, Mitochondrial drug effects
Mitochondria metabolism
Multiple Myeloma metabolism
Myeloid Cell Leukemia Sequence 1 Protein metabolism
NF-kappa B antagonists & inhibitors
NF-kappa B metabolism
Oligopeptides pharmacology
Peptides isolation & purification
Peptides urine
Phenylacetates isolation & purification
Phenylacetates urine
Poly(ADP-ribose) Polymerases metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Transcription Factor RelA metabolism
X-Linked Inhibitor of Apoptosis Protein metabolism
bcl-2-Associated X Protein metabolism
Antineoplastic Agents pharmacology
Apoptosis drug effects
Mitochondria drug effects
Multiple Myeloma pathology
Peptides pharmacology
Phenylacetates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1791-3004
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular medicine reports
- Publication Type :
- Academic Journal
- Accession number :
- 24452179
- Full Text :
- https://doi.org/10.3892/mmr.2014.1911