Abstract
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.
Highlights
Chemotherapy and radiotherapy (RT) are common treatments used to decrease the tumor burden and to ameliorate tumorrelated symptoms
Phospholipase D (PLD) inhibition in combination with radiation inhibits cell growth in breast cancer cells Both the PLD1- and the PLD2-selective inhibitors induced cytotoxicity in a dose-dependent manner in MBA-MB-231 cells when treated for 72 h (Figure 1a)
The slopes of the survival curves of the MDAMB-231 cells treated with a combination of radiation and either the PLD1 or the PLD2 inhibitor were greater than those of the cells treated with radiation alone, indicating that the combined treatment increased the cell’s sensitivity to radiation, resulting in a decrease in the surviving fraction of cells (Figure 1d)
Summary
Chemotherapy and radiotherapy (RT) are common treatments used to decrease the tumor burden and to ameliorate tumorrelated symptoms. The current regimes are not curative in most cases and, in general, cancer mortality rates have not decreased significantly in recent years.[1] This situation has prompted many researchers and companies to develop novel compounds that possess higher and more selective antitumor activities. Radiation therapy plays a critical role in the local and regional control of malignant tumors. Recent attempts to enhance the efficacy of radiation therapy have focused on using conventional chemotherapeutic agents as biological response modifiers.[2]. Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid, which activates a signaling cascade leading to cell growth, survival and angiogenesis.[3] Two mammalian isoforms of phosphatidylcholinespecific PLD (that is, PLD1 and PLD2) have been identified. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival
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