Loratadine deregulates cell cycle progression and enhances the effect of radiation in human tumor cell lines
ft is well established that the effects regulated by a complex network of nuclear translocation of Cdc25C, of radiation varies as a function of proteins that monitor the health of and Chk1 phosphorylation, which cell cycle position. Specifically, the cell. This mechanism serves to allows 14-3-3 binding to occur. cells in d2/M phase are particularly protect cells from potentially lethal Chk1 inhibition has been associated susceptible to the effects of stressors by temporarily halting cell with increased cytotoxicity of DNA radiation. Because of this, agents cycle progression to allow time for damaging drugs, and in our lab with that alter cell cycle progression are repair of damaged cell components, increased sensitivity to the effects often potent radiation modifiers. especially damage involving DNA. of radiation (unpublished dataF. Normal cell cycle regulation is For example, it is well known that Recently, loratadine has also been mediated by several proteins that DNA damage induced by radiation shown to cause Cdc2-associated are responsive to both intra- and results in cell cycle block in G2/M G2/M arrest by interfering with Chk1 extracellular stimuli. ft has been during which time the DNA repair and Cdc25C signaling. It is likely that demonstrated that the commonly machinery attempts to correct the the anti-tumor effects of loratadine used antihistamine loratadine damage. If the damage is repaired, observed in other studies result, at (ethyl4-(8-chloro-5,6-dihydrocells are released from the cell least in part, from this activity. NNe-benzo cyclohepta pyridin-NNcycle block and are allowed to pince d2/M is a particularly ylidene)-1-piperidinecarboxylate), divide. Persistent DNA damage radiosensitive phase of the cell an antagonist of histamine may result in cell death initiated by cycle, it is logical to suggest that receptor-1, induces a cell cycle other surveillance mechanisms. fn the induction of a cell cycle block in arrest in G2/M by interfering with eukaryotic cells, the G2/M checkpoint d2/M by loratadine would enhance the activity of these regulatory is controlled by several proteins radiation-induced cytotoxicity, proteins. Although a comprehensive including cell division cycle 2 (Cdc2) however this has not yet been studied. mechanism was not elucidated, and Cycling B. Cdc2 is inactivated This study was initiated to determine in these prior studies loratadine by phosphorylation (Tyr-15, Thr-14) whether loratadine modifies the treatment resulted in anti-tumor and activated by Cdc25C-mediated effect of radiation on cell survival effects. dephosphorylating. Cdc25C, in turn, and, if so, to elucidate the mechanism Progression through the cell cycle is is regulated by 14-3-3, which inhibits underlying that effect.