Abstract
Reactive oxygen species (ROS) have a crucial role in cell signaling and cellular functions. Mounting evidences suggest that abnormal increase of ROS is often observed in cancer cells and that this biochemical feature can be exploited for selective killing of the malignant cells. A naturally occurring compound phenethyl isothiocyanate (PEITC) has been shown to have promising anticancer activity by modulating intracellular ROS. Here we report a novel synthetic analog of PEITC with superior in vitro and in vivo antitumor effects. Mechanistic study showed that LBL21 induced a rapid depletion of intracellular glutathione (GSH), leading to abnormal ROS accumulation and mitochondrial dysfunction, evident by a decrease in mitochondrial respiration and transmembrane potential. Importantly, LBL21 exhibited the ability to abrogate stem cell-like cancer side population (SP) cells in non-small cell lung cancer A549 cells associated with a downregulation of stem cell markers including OCT4, ABCG2, SOX2 and CD133. Functionally, LBL21 inhibited the ability of cancer cells to form colonies in vitro and develop tumor in vivo. The therapeutic efficacy of LBL21 was further demonstrated in mice bearing A549 lung cancer xenografts. Our study suggests that the novel ROS-modulating agent LBL21 has promising anticancer activity with an advantage of elimination of stem-like cancer cells. This compound merits further study to evaluate its potential for use in cancer treatment.
Highlights
Cancer cells exhibit various differences in cellular biological activities, including the level of reactive oxygen species (ROS), which is involved in redox balance, cellular proliferation, cancer progression and cancer stem cells (CSCs).[1,2] The elevated level of ROS in cancer cells is often considered as an adverse factor to cause genetic instability
It is well known that malignant cancer cells have increased ROS level and are more dependent on endogenous antioxidant to maintain a redox balance for cell survival, suggesting that
A ROS scavenger NAC was able to reverse the cell apoptosis caused by LBL21, further suggesting LBL21-induced cell death may result from excessive ROS production
Summary
Cancer cells exhibit various differences in cellular biological activities, including the level of reactive oxygen species (ROS), which is involved in redox balance, cellular proliferation, cancer progression and cancer stem cells (CSCs).[1,2] The elevated level of ROS in cancer cells is often considered as an adverse factor to cause genetic instability. In recent years, growing evidences suggest that CSCs, a small subgroup of special cancer cells, have high self-renewal capability and have important roles in maintaining tumor growth and causing drug resistance.[7,8] CSCs in tumors contain low ROS levels compared with nontumorigenic cells because of their increased antioxidant capacity to defend ROS stress.[9] As a consequence, pharmacologically targeting ROS defense system, for example, excessively increasing ROS level could reduce clonogenicity and mediate death of CSCs.[10]. Phenethyl isothiocyanates (PEITC), a naturally occurring compound widely present in cruciferous vegetables, is able to modulate excessive ROS generation and selectively kill cancer cells.[11] Previous studies have demonstrated that PEITC killed malignant cancer cells by disabling glutathione (GSH) antioxidant system and disrupting redox-sensitive survival pathways.[10,12] PEITC has been registered in clinical trials for cancer prevention and treatment (ClinicalTrials.gov Identifiers: NCT00005883, NCT00691132 and NCT01790204), indicating that PEITC could hold a therapeutic promise to treat cancer patients. The anticancer effect is further demonstrated in subsequent in vivo study with mice bearing A549 lung cancer xenografts
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