title: Down-regulation of the nuclear factor-kappaB by lidamycin in association with inducing apoptosis in human pancreatic cancer cells and inhibiting xenograft growth.
abstract: Pancreatic cancer is now one of the most common causes of cancer death worldwide. K-ras mutations are present in up to 90% of pancreatic cancer cases. The expression of mutant K-ras activates the Akt/protein kinase B pathway, resulting in the activation of the nuclear factor-kappaB (NF-kappaB) transcriptional factor. Constitutive NF-kappaB activity plays a key role in pancreatic carcinoma. NF-kappaB has been shown to inhibit apoptosis in response to chemotherapeutic agents. In the present study, the effects of lidamycin (LDM), a member of the enediyne antibiotic family, were investigated on two established pancreatic cell lines, PANC-1 and SW1990. A dose-dependent inhibition of phospho-Akt and NF-kappaB activation was found in the cells treated with LDM as determined by Western blot analysis. Moreover, a down-regulation of K-ras mRNA and a protein expression by LDM were observed in both cell lines as determined by reverse transcription-PCR and Western blot analysis. By MTT assay, a remarkable difference in chemosensitivity to LDM, mitomycin, adriamycin, taxol, and gemcitabine was found in both cell lines. The IC50 values of LDM for the PANC-1 or SW1990 cells were 0.955+/-0.414 or 0.426+/-0.212 nM, respectively, lower than those of the other drugs. Growth inhibition, apoptosis induction and cell cycle arrest were observed in the LDM-treated cells. LDM decreased the invasive potential of pancreatic cancer cells by reducing matrix metalloproteinase-9 activity. Furthermore, LDM was found to suppress the growth of SW1990 xenografts in nude mice. Treatment with an i.v. injection of LDM at the dose of 0.02 and 0.04 mg/kg (once a week for two weeks) inhibited the growth of xenografts by 66 and 72%, respectively. By contrast, an i.p. injection of gemcitabine at the dose of 80 mg/kg inhibited the growth of xenografts by 38%. Our findings suggest that LDM is active in the down-regulation of NF-kappaB and could play a positive role in relevant targeted chemotherapy for pancreatic carcinoma.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Ouyang
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Zhang
authors.forename: Yong-Su
authors.initials: YS
authors.lastname: Zhen
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D053281:Enediynes / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D016328:NF-kappa B; D012333:RNA, Messenger; C058024:C 1027; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)