Enediyne lidamycin induces apoptosis in human multiple myeloma cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase.
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.
Zhen
Yong-Zhan
YZ
Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, #1 Tian Tan Xi Li, 100050, Beijing, China.|North China Coal Medical College, Tangshan, Hebei, China.
Lin
Ya-Jun
YJ
Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, #1 Tian Tan Xi Li, 100050, Beijing, China.
Shang
Bo-Yang
BY
Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, #1 Tian Tan Xi Li, 100050, Beijing, China.
Zhen
Yong-Su
YS
Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, #1 Tian Tan Xi Li, 100050, Beijing, China. zhenys@public.bta.net.cn.
D000617:Aminoglycosides / Q000494:pharmacology* / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D053281:Enediynes / Q000494:pharmacology* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D009363:Neoplasm Proteins; C058024:C 1027; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D053179:Caspase 7