Lidamycin induces marked G2 cell cycle arrest in human colon carcinoma HT-29 cells through activation of p38 MAPK pathway

Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, P.R. China.
Oncology Reports (Impact Factor: 2.3). 04/2007; 17(3):597-603. DOI: 10.3892/or.17.3.597
Source: PubMed


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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    • "Recent studies have indicated that LDM induces unusual DNA damage responses to double-strand breaks16. It alters cell cycle progression and induces chromosomal aberrations17, 18. As reported, the antitumor effect of LDM could be amplified by other agents19. "
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    Acta Pharmacologica Sinica 08/2009; 30(7):1025-32. DOI:10.1038/aps.2009.75 · 2.91 Impact Factor
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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. DOI:10.2174/1874467210801010050
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    ABSTRACT: Recent advances in cell cycle regulation have led to a suggestion of therapeutically targeting cell cycle checkpoint pathways in cancer cells to increase the toxicity of DNA-damaging agents. In this study, we investigate whether knockdowns of checkpoint kinases Chk1 and Chk2 by RNA interfering potentiate the cytotoxicity and abrogate G(2)/M checkpoint induced by DNA-damaging agent lidamycin (LDM) in HCT116 cells with different p53 status. Our results showed that Chk1 knockdown enhanced the cytotoxicity of LDM through abrogating G(2)/M arrest and increasing apoptosis to a greater extent in HCT116 p53(-/-) cells than in p53(wt) cells. Abrogation of LDM-induced G(2)/M arrest by Chk1 knockdown was associated with reducing the inactivated phosphorylations of Cdc25C and Cdc2. LDM-induced gamma-H2AX was increased in cells with Chk1 knockdown, indicating that DNA double-strand breaks (DSBs) were enhanced. Furthermore, knockdown of Chk1 also increased LDM-mediated apoptotic cell death in p53 knockout cells with activation of caspase-2 and caspase-3. On the contrary, knockdown of Chk2 had no impact on G(2)/M arrest or apoptosis induced by LDM. Moreover, dual knockdown of Chk1 and Chk2 failed to achieve better efficacy than Chk1 alone. Taken together, we suggest that Chk1 is a potential therapeutic target to sensitize human p53 deficient cancer cells to LDM.
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