Abstract
The current study investigated the effects of Piper longumine on radio-sensitization of human breast cancer MDA-MB-231 cells and underlying mechanisms. Human breast cancer MDA-MB-231 cells were cultured in vitro and those in logarithmic growth phase were selected for experiments divided into four groups: control, X-ray exposed, Piper longumine, and Piper longumine combined with X-rays. Conogenic assays were performed to determine the radio-sensitizing effects. Cell survival curves were fitted by single-hit multi-target model and then the survival fraction (SF), average lethal dose (D0), quasi-threshold dose (Dq) and sensitive enhancement ratio (SER) were calculated. Cell apoptosis was analyzed by flow cytometry (FCM).Western blot assays were employed for expression of apoptosis-related proteins (Bc1-2 and Bax) after treatment with Piper longumine and/or X-ray radiation. The intracellular reactive oxygen species (ROS) level was detected by FCM with a DCFH-DA probe. The cloning formation capacity was decreased in the group of piperlongumine plus radiation, which displayed the values of SF2, D0, Dq significantly lower than those of radiation alone group and the sensitive enhancement ratio (SER) of D0 was1.22 and 1.29, respectively. The cell apoptosis rate was increased by the combination treatment of Piper longumine and radiation. Piper longumine increased the radiation-induced intracellular levels of ROS. Compared with the control group and individual group, the combination group demonstrated significantly decreased expression of Bcl-2 with increased Bax. Piper longumine at a non-cytotoxic concentration can enhance the radio-sensitivity of MDA- MB-231cells, which may be related to its regulation of apoptosis-related protein expression and the increase of intracellular ROS level, thus increasing radiation-induced apoptosis.
Highlights
Triple-negative breast cancer (TNBC), a subtype of breast cancers, is defined by lack of both protein expression of estrogen receptor (ER), progesterone receptor (PR) and over-expression of human epidermal growth factor receptor-2 (HER-2)
Cell apoptosis was analyzed by flow cytometry (FCM).Western blot assays were employed for expression of apoptosis-related proteins (Bc1-2 and Bax) after treatment with Piper longumine and/or X-ray radiation
We focus on three aspects: 1) Whether Piper longumine (PL) has the potential to enhance radio-sensitivity of MDA-MB-231 cells; 2) Whether it is accomplished by increasing apoptosis; 3) The underlying further molecular mechanisms of radio-sensitivity
Summary
Triple-negative breast cancer (TNBC), a subtype of breast cancers, is defined by lack of both protein expression of estrogen receptor (ER), progesterone receptor (PR) and over-expression of human epidermal growth factor receptor-2 (HER-2). Its antitumor functions have been investigated in breast cancer (Yao et al, 2013), HL-60 leukemia (Kong et al, 2008), and prostate cancer cells line (Bezerra et al, 2007) by the way of changing cell cycles and inducing apoptosis through elevating reactive oxygen species (ROS) production. Despite widespread investigation into the direct antitumor effect of PL (Bezerra et al, 2007; Kong et al, 2008; Yao et al, 2013), there is little data regarding the effect of PL as a radiosensitizer for antitumor therapy and the literature is silent on the enhancement of radio-sensitivity of PL on breast adenoma cells. A safe and effective radio-sensitizing agent may allow a decrease in the radiation dose and side effects associated with RT for advanced TNBC. We focus on three aspects: 1) Whether PL has the potential to enhance radio-sensitivity of MDA-MB-231 cells; 2) Whether it is accomplished by increasing apoptosis; 3) The underlying further molecular mechanisms of radio-sensitivity
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