Abstract
BackgroundIt was well known that the clinical use of chemotherapeutic drugs is restricted by severe adverse reactions and drug resistances. Thus it is necessary to figure out a strategy to increase the specific anti-tumor efficiency of chemotherapeutic drugs. Apigenin, a kind of flavonoids, has been reported to possess anticancer activities with very low cytotoxicity to normal tissue.Methodology/Principal FindingsOur results from cell viability assay, western-blots and TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay demonstrated the synergistic pro-apoptotic effects of a low dose of apigenin and paclitaxel in human cancer cell lines. To analyze the underlying mechanism, we examined reactive oxygen species (ROS) staining after cells were treated with a combination of apigenin and paclitaxel, or each of them alone. Data from flow-cytometry showed that superoxides but not reduction of peroxides accumulated in HeLa cells treated with apigenin or a combination of apigenin and paclitaxel. Apigenin and paclitaxel-induced HeLa cell apoptosis was related to the level of ROS in cells. We further evaluated activity and protein level of superoxide dismutase (SOD). Apigenin significantly inhibited SOD activity but did not alter the SOD protein level suggesting that apigenin promoted ROS accumulation through suppressing enzyme activity of SOD. Addition of Zn2+, Cu2+ and Mn2+ to cell lysates inhibited apigenin's effects on SOD activity. At the same time, data from caspase-2 over-expression and knocked-down experiments demonstrated that caspase-2 participated in apigenin and paclitaxel-induced HeLa cell apoptosis.Conclusions/SignificanceTaken together, our study demonstrated that apigenin can sensitize cancer cells to paclitaxel induced apoptosis through suppressing SOD activity, which then led to accumulation of ROS and cleavage of caspase-2, suggesting that the combined use of apigenin and paclitaxel was an effective way to decrease the dose of paclitaxel taken.
Highlights
Chemotherapy is one of the most widely employed treatments for cancer
Conclusions/Significance: Taken together, our study demonstrated that apigenin can sensitize cancer cells to paclitaxel induced apoptosis through suppressing superoxide dismutase (SOD) activity, which led to accumulation of Reactive oxygen species (ROS) and cleavage of caspase-2, suggesting that the combined use of apigenin and paclitaxel was an effective way to decrease the dose of paclitaxel taken
We demonstrated that apigenin could sensitize cancer cells to paclitaxel induced apoptosis through suppressing SOD activity and leading to accumulation of ROS and cleavage of caspase-2, suggesting the combined use of apigenin and paclitaxel was effective for cancer therapy
Summary
Chemotherapy is one of the most widely employed treatments for cancer. many chemotherapeutic drugs can produce unpleasant side effects,especially when taken in high doses. Reactive oxygen species (ROS) including superoxide radical, hydrogen peroxide (H2O2), hydroxyl radical, nitric oxide, and various nitric oxide-derived reactive nitro species (RNS) are formed as natural byproducts of normal metabolism of oxygen in human cells and tissues. Because of their highly reactive character, they tend to become involved in unwanted reactions that cause damage to cells and lead to diseases. A high cell redox state would support increased apoptosis, which would inhibit tumor formation. In cancer cells, the high redox state could enhance their tolerance to environmental stresses and chemotherapeutic drugs. A kind of flavonoids, has been reported to possess anticancer activities with very low cytotoxicity to normal tissue
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