Lidamycin induces marked G2 cell cycle arrest in human colon carcinoma HT-29 cells through activation of p38 MAPK pathway.
ABSTRACT Lidamycin (LDM), a member of the enediyne antibiotic family, is presently undergoing phase I clinical trials in P.R. China. In this study, we investigated the mechanisms of LDM-induced cell cycle arrest in order to support its use in clinical cancer therapy. Using human colon carcinoma HT-29 cells, we observed that LDM induced G2 cell cycle arrest in a time- and dose-dependent manner. LDM-induced G2 arrest was associated with increasing phosphorylation of Chk1, Chk2, Cdc25C, Cdc2 and expression of Cdc2 and cyclin B1. In addition, cytoplasmic localization of cyclin B1 was also involved in LDM-induced G2 arrest. Moreover, we found that p38 MAPK pathway contributed to LDM-induced G2 arrest. Inhibition of p38 MAPK by its inhibitor SB203580 not only attenuated LDM-induced G2 arrest but also potentiated LDM-induced apoptosis, which was accompanied by decreasing phosphorylation of Cdc2 and increasing expression of FasL and phosphorylation of JNK. Finally, we demonstrated that cells at G1 phase were more sensitive to LDM. Together, our findings suggest that p38 MAPK signaling pathway is involved in LDM-induced G2 arrest, at least partly, and a combination of LDM with p38 MAPK inhibitor may represent a new strategy for human colon cancer therapy.
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ABSTRACT: The natural compounds that interfere with cellular DNA such as enediyne antitumor antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the enediyne antitumor agents that are approved for clinical use and undergoing pre-clinical or clinical evaluation are reviewed. Most enediyne compounds have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to other chemotherapeutic drugs. Enediyne derivatives, such as an immunoconjugate composed of an enediyne compound and monoclonal antibody, reveal stronger activity and selectivity for human cancer cells. The mechanism underlying the anticancer activity of these enediyne antitumor agents may mainly lie in their generation of DNA double-strand breaks. Increasing evidence shows that the enediyne-induced DNA double-strand breaks can engage the activation of DNA damage response proteins, arresting cell cycle progression and eventually leading to apoptotic cell death. Continued investigation of the mechanisms of action and development of new enediyne derivatives and conjugates may provide more effective therapeutics for cancer treatments.Current Molecular Pharmacology 01/2008; 1(1):50-60.
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ABSTRACT: To investigate the effects of lidamycin (LDM) on a mouse myeloma cell line (SP2/0) and human multiple myeloma cell lines (U266 and SKO-007), and provide the basis for the use of LDM in cancer therapy. A 3-[4,5-dimethylthiazol-2-yl]5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]2H-tetrazolium inner salt (MTS) assay was used to determine the degree of growth inhibition by the drugs analyzed in this study. Cell cycle distribution and analysis were measured by flow cytometry combined with propidium iodide (PI) staining. The effects on apoptosis were measured by Hoechst 33342 staining and by flow cytometry combined with fluorescein-isothiocyanate-Annexin V/propidium iodide (FITC-Annexin V/PI) staining. Protein expression was determined by Western blot analysis. In vivo antitumor activity was measured using a murine myeloma model in BALB/c mice. There was a significant reduction in cell proliferation after treatment with LDM. The overall growth inhibition correlated with increased apoptotic cell death. LDM-induced cell apoptosis was associated with the activation of c-Jun-N-terminal kinase (JNK), and cleavage of caspase-3/7 and poly (ADP-ribose) polymerase (PARP). LDM markedly suppressed tumor growth in a murine myeloma model. LDM induces apoptosis in murine myeloma SP2/0 cells as well as in human myeloma U266 and SKO-007 cell lines. The sustained activation of JNK might play a critical role in LDM-induced apoptosis in the SP2/0 cell line. LDM demonstrates significant antitumor efficacy against myeloma SP2/0 cells in mice. Taken together, our data provide some clues for further research of the effects of LDM on human multiple myeloma.Acta Pharmacologica Sinica (2009) 30: 1025-1032; doi: 10.1038/aps.2009.75.Acta Pharmacologica Sinica 08/2009; 30(7):1025-32. · 2.35 Impact Factor