選擇性殺傷腫瘤細胞而減輕對正常組織的損傷是目前治療腫瘤策略所面臨的重大挑戰(zhàn),。研究表明,，由于腫瘤細胞的快速增殖，實體瘤細胞通常處于氧氣,、葡萄糖或其他營養(yǎng)物質(zhì)匱乏的狀態(tài),。因此，靶向葡萄糖缺乏的腫瘤細胞可能會成為選擇性殺傷腫瘤細胞的一個新策略,。
牛蒡子苷元是臨床常用傳統(tǒng)中藥牛蒡子的主要活性成分?，F(xiàn)有研究表明，牛蒡子苷元具有抗腫瘤活性,，能夠在多種腫瘤模型中有效抑制腫瘤生長,。中科院上海藥物研究所俞強課題組對牛蒡子苷元的抗腫瘤機制進行了深入研究,，發(fā)現(xiàn)在葡萄糖缺乏條件下，牛蒡子苷元通過抑制線粒體呼吸造成腫瘤細胞內(nèi)ATP水平下降以及活性氧族水平升高,，從而促使腫瘤細胞死亡,。
研究同時還發(fā)現(xiàn)，牛蒡子苷元和糖酵解抑制劑2-脫氧-D-葡萄糖聯(lián)合使用能夠選擇性殺傷腫瘤細胞,，而對正常細胞的毒性較低,。
該項研究成果為用中藥治療腫瘤提供了新的依據(jù)和策略。相關(guān)論文已在線發(fā)表于Biochemical Pharmacology雜志,。
該研究工作得到了國家自然科學(xué)基金和國家重大科技專項的資助,。(生物谷Bioon.com）
doi.org/10.1016/j.bcp.2012.06.002
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PMID:
Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism
Yuan Gua， Chunting Qia,， Xiaoxiao Suna,， Xiuquan Mab， Haohao Zhanga,， Lihong Huc,， Junying Yuand， Qiang Yua,，
a Department of Tumor Pharmacology,， Shanghai Institute of Materia Medica， Chinese Academy of Sciences,， Shanghai,， China
b Department of Bioorganic Chemistry， Shanghai Institute of Organic Chemistry,， Chinese Academy of Sciences,， Shanghai， China
c State Key Laboratory of Drug Research,， Shanghai Institute of Materia Medica,， Chinese Academy of Sciences， Shanghai,， China
d Department of Cell Biology,， Harvard Medical School， Boston,， USA
Abstract
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.
