Abstract |
In the present study, the effects of lidamycin (LDM), a member of the enediyne antibiotic family, on two human multiple myeloma (MM) cell lines, U266 and SKO-007, were evaluated. In MTS assay, LDM showed much more potent cytotoxicity than conventional anti-MM agents to both cell lines. The IC(50) values of LDM for the U266 and SKO-007 cells were 0.0575 +/- 0.0015 and 0.1585 +/- 0.0166 nM, respectively, much lower than those of adriamycin, dexamethasone, and vincristine. Mechanistically, LDM triggered MM cells apoptosis by increasing the levels of cleaved poly ADP-ribose polymerase (PARP) and caspase-3/7. In addition, activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) was a critical mediator in LDM-induced cell death. Inhibition of the expression of p38 MAPK and JNK by pharmacological inhibitors reversed the LDM-induced apoptosis through decreasing the level of cleaved PARP and caspase-3/7. Interestingly, phosphorylation of extracellular signal-related kinase was increased by LDM; conversely, MEK inhibitor synergistically enhanced LDM-induced cytotoxicity and apoptosis in MM cells. The results demonstrated that LDM suppresses MM cell growth through the activation of p38 MAPK and JNK, with the potential to be developed as a chemotherapeutic agent for MM.
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Authors | Yong-Zhan Zhen, Ya-Jun Lin, Bo-Yang Shang, Yong-Su Zhen |
Journal | International journal of hematology
(Int J Hematol)
Vol. 90
Issue 1
Pg. 44-51
(Jul 2009)
ISSN: 1865-3774 [Electronic] Japan |
PMID | 19468799
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Aminoglycosides
- Antibiotics, Antineoplastic
- Enediynes
- Neoplasm Proteins
- C 1027
- Poly(ADP-ribose) Polymerases
- JNK Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- CASP3 protein, human
- Caspase 3
- Caspase 7
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Topics |
- Aminoglycosides
(pharmacology, therapeutic use)
- Antibiotics, Antineoplastic
(pharmacology, therapeutic use)
- Apoptosis
(drug effects)
- Caspase 3
(metabolism)
- Caspase 7
(metabolism)
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Enediynes
(pharmacology, therapeutic use)
- Enzyme Activation
(drug effects)
- Humans
- JNK Mitogen-Activated Protein Kinases
(metabolism)
- Multiple Myeloma
(drug therapy, enzymology)
- Neoplasm Proteins
(metabolism)
- Poly(ADP-ribose) Polymerases
(metabolism)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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