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Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity
ACS Central Science ( IF 12.7 ) Pub Date : 2017-06-28 00:00:00 , DOI: 10.1021/acscentsci.7b00156 Jigang Wang 1, 2, 3 , Jianbin Zhang 1 , Yin Shi 1 , Chengchao Xu 3 , Chongjing Zhang 3, 4 , Yin Kwan Wong 1 , Yew Mun Lee 3 , Sanjeev Krishna 5 , Yingke He 6 , Teck Kwang Lim 3 , Weiying Sim 3 , Zi-Chun Hua 2 , Han-Ming Shen 1 , Qingsong Lin 3
ACS Central Science ( IF 12.7 ) Pub Date : 2017-06-28 00:00:00 , DOI: 10.1021/acscentsci.7b00156 Jigang Wang 1, 2, 3 , Jianbin Zhang 1 , Yin Shi 1 , Chengchao Xu 3 , Chongjing Zhang 3, 4 , Yin Kwan Wong 1 , Yew Mun Lee 3 , Sanjeev Krishna 5 , Yingke He 6 , Teck Kwang Lim 3 , Weiying Sim 3 , Zi-Chun Hua 2 , Han-Ming Shen 1 , Qingsong Lin 3
Affiliation
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The antimalarial artemisinin (ART) possesses anticancer activity, but its underlying mechanism remains largely unclear. Using a chemical proteomics approach with artemisinin-based activity probes, we identified over 300 specific ART targets. This reveals an anticancer mechanism whereby ART promiscuously targets multiple critical biological pathways and leads to cancer cell death. The specific cytotoxicity of ART against colorectal cancer (CRC) cells rather than normal colon epithelial cells is due to the elevated capacity of heme synthesis in the cancer cells. Guided by this mechanism, the specific cytotoxicity of ART toward CRC cells can be dramatically enhanced with the addition of aminolevulinic acid (ALA), a clinically used heme synthesis precursor, to increase heme levels. Importantly, this novel ART/ALA combination therapy proves to be more effective than an ART monotherapy in a mouse xenograft CRC model. Thus, ART can be repurposed and potentiated by exploitation of its mechanism of action and the metabolic features of the CRC cells.
中文翻译：
青蒿素及其与氨基乙酰丙酸联用增强抗结直肠癌活性的机制研究
抗疟疾青蒿素（ART）具有抗癌活性，但其基本机制仍不清楚。使用基于青蒿素的活性探针的化学蛋白质组学方法，我们确定了300多个特定的ART靶标。这揭示了一种抗癌机制，其中ART混杂地靶向多种关键的生物途径并导致癌细胞死亡。ART对结直肠癌细胞（CRC）而非正常结肠上皮细胞的特异性细胞毒性是由于癌细胞中血红素合成能力的提高。在这种机制的指导下，可通过添加氨基乙酰丙酸（ALA）（一种临床上使用的血红素合成前体）来增加血红素水平，从而显着增强ART对CRC细胞的特异性细胞毒性。重要的，在小鼠异种移植CRC模型中，这种新颖的ART / ALA联合疗法被证明比ART单一疗法更有效。因此，ART可以通过利用其作用机理和CRC细胞的代谢特征而被重新利用和增强。
更新日期：2017-07-28
中文翻译：
青蒿素及其与氨基乙酰丙酸联用增强抗结直肠癌活性的机制研究
抗疟疾青蒿素（ART）具有抗癌活性，但其基本机制仍不清楚。使用基于青蒿素的活性探针的化学蛋白质组学方法，我们确定了300多个特定的ART靶标。这揭示了一种抗癌机制，其中ART混杂地靶向多种关键的生物途径并导致癌细胞死亡。ART对结直肠癌细胞（CRC）而非正常结肠上皮细胞的特异性细胞毒性是由于癌细胞中血红素合成能力的提高。在这种机制的指导下，可通过添加氨基乙酰丙酸（ALA）（一种临床上使用的血红素合成前体）来增加血红素水平，从而显着增强ART对CRC细胞的特异性细胞毒性。重要的，在小鼠异种移植CRC模型中，这种新颖的ART / ALA联合疗法被证明比ART单一疗法更有效。因此，ART可以通过利用其作用机理和CRC细胞的代谢特征而被重新利用和增强。
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