Radiation and drug resistance remain the major challenges and causes of mortality in the treatment of locally advanced, recurrent and metastatic breast cancer. Dysregulation of phospholipase D (PLD) has been found in several human cancers and is associated with resistance to anticancer drugs. In the present study, we evaluated the effects of PLD inhibition on cell survival, cell death and DNA damage after exposure to ionizing radiation (IR). Combined IR treatment and PLD inhibition led to an increase in the radiation-induced apoptosis of MDA-MB-231 metastatic breast cancer cells. The selective inhibition of PLD1 and PLD2 led to a significant decrease in the IR-induced colony formation of breast cancer cells. Moreover, PLD inhibition suppressed the radiation-induced activation of extracellular signal-regulated kinase and enhanced the radiation-stimulated phosphorylation of the mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. Furthermore, PLD inhibition, in combination with radiation, was very effective at inducing DNA damage, when compared with radiation alone. Taken together, these results suggest that PLD may be a useful target molecule for the enhancement of the radiotherapy effect.
Breast Neoplasms/*drug therapy/*enzymology/pathology ; Cell Death/drug effects/radiation effects ; Cell Line, Tumor ; Cell Proliferation/drug effects/radiation effects ; DNA Damage ; Enzyme Activation/drug effects/radiation effects ; Enzyme Inhibitors/*pharmacology/*therapeutic use ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Phospholipase D/*antagonists & inhibitors/metabolism ; Radiation Tolerance/*drug effects ; Radiation, Ionizing ; p38 Mitogen-Activated Protein Kinases/metabolism

Fucoidan is a sulfated polysaccharide purified from brown algae including Fucus vesiculosus and has a variety of biological effects including mobilization of hematopoietic progenitor cells. Recently, we demonstrated that fucoidan stimulates the antigen-presenting functions of dendritic cells. In this study, we investigated the radioprotective effects of fucoidan on bone marrow cells (BMCs), which are the main cellular reservoir for the hematopoietic and immune system. To evaluate the effects of fucoidan, we assayed cell viability and immune responses. In a viability assay, fucoidan significantly increased the viability of BMCs. Based on the results of flow cytometric analysis, the increased viability of fucoidan-treated BMCs was attributed to the inhibition of radiation-induced apoptosis. Furthermore, fucoidan altered the production of immune-related cytokines from BMCs and increased the capability of BMCs to induce proliferation of allogeneic splenocytes. Taken together, our study demonstrated that fucoidan has radioprotective effects on BMCs with respect to cell viability and immunoreactivity. These results may provide valuable information, useful in the field of radiotherapy.
Animals ; Bone Marrow Cells/*drug effects/*radiation effects ; Cell Death/drug effects/radiation effects ; Cell Proliferation ; Cell Survival/drug effects ; Cells, Cultured ; Female ; Gamma Rays/*adverse effects ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Polysaccharides/*pharmacology ; Radiation-Protective Agents/*pharmacology ; Spleen/cytology