Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism.
Selectively eradicating cancer cells with minimum adverse effects on normal cells is a major challenge in the development of anticancer therapy. We hypothesize that nutrient-limiting conditions frequently encountered by cancer cells in poorly vascularized solid tumors might provide an opportunity for developing selective therapy. In this study, we investigated the function and molecular mechanisms of a natural compound, arctigenin, in regulating tumor cell growth. We demonstrated that arctigenin selectively promoted glucose-starved A549 tumor cells to undergo necrosis by inhibiting mitochondrial respiration. In doing so, arctigenin elevated cellular level of reactive oxygen species (ROS) and blocked cellular energy metabolism in the glucose-starved tumor cells. We also demonstrated that cellular ROS generation was caused by intracellular ATP depletion and played an essential role in the arctigenin-induced tumor cell death under the glucose-limiting condition. Furthermore, we combined arctigenin with the glucose analogue 2-deoxyglucose (2DG) and examined their effects on tumor cell growth. Interestingly, this combination displayed preferential cell-death inducing activity against tumor cells compared to normal cells. Hence, we propose that the combination of arctigenin and 2DG may represent a promising new cancer therapy with minimal normal tissue toxicity.
Department of Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Yuan
Y
Gu
Chunting
C
Qi
Xiaoxiao
X
Sun
Xiuquan
X
Ma
Haohao
H
Zhang
Lihong
L
Hu
Junying
J
Yuan
Qiang
Q
Yu
D000255:Adenosine Triphosphate / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D031170:Arctium / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D005663:Furans / Q000302:isolation & purification / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D059016:Tumor Microenvironment
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D017705:Lignans; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D005947:Glucose; C071942:arctigenin