Selective Targeting of Cancer Cells by Oxidative Vulnerabilities with Novel Curcumin Analogs.
Selective Targeting of Cancer Cells by Oxidative Vulnerabilities with Novel Curcumin Analogs.
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DOI：
10.1038/s41598-017-01230-4
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发表时间：
2017-04-24
影响因子：
4.6
通讯作者：
Pandey S
中科院分区：
文献类型：
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作者：
Pignanelli C;Ma D;Noel M;Ropat J;Mansour F;Curran C;Pupulin S;Larocque K;Wu J;Liang G;Wang Y;Pandey S
最近，研究的重点是针对癌细胞中的氧化和代谢脆弱性。针对此类易感性的天然化合物（如姜黄素）由于稳定性和生物利用度较差以及需要高有效剂量，未能取得进一步的临床进展。我们合成了几种姜黄素单羰基类似物，并对其抗癌活性进行了评价。有趣的是，与姜黄素相比，两种新的类似物（化合物A和I）具有增加的化学稳定性，并且在多种人类癌细胞（包括三阴性炎性乳腺癌细胞）中具有更大的抗癌活性。特别是，活性氧的产生对癌细胞具有选择性，并发生在线粒体崩溃和细胞凋亡的上游。此外，化合物A与另一种癌症选择性/促氧化剂piperlongumine组合引起增强的抗癌作用。最重要的是，化合物A被小鼠良好耐受，并且当腹膜内施用时，在体内有效抑制人三阴性乳腺癌和白血病异种移植物的生长。因此，利用癌细胞中的氧化脆弱性可能是一种选择性和有效的手段，以消除恶性细胞，如本报告中提出的具有高治疗潜力的姜黄素类似物所证明的。
Recently, research has focused on targeting the oxidative and metabolic vulnerabilities in cancer cells. Natural compounds like curcumin that target such susceptibilities have failed further clinical advancements due to the poor stability and bioavailability as well as the need of high effective doses. We have synthesized and evaluated the anti-cancer activity of several monocarbonyl analogs of curcumin. Interestingly, two novel analogs (Compound A and I) in comparison to curcumin, have increased chemical stability and have greater anti-cancer activity in a variety of human cancer cells, including triple-negative, inflammatory breast cancer cells. In particular, the generation of reactive oxygen species was selective to cancer cells and occurred upstream of mitochondrial collapse and execution of apoptosis. Furthermore, Compound A in combination with another cancer-selective/pro-oxidant, piperlongumine, caused an enhanced anti-cancer effect. Most importantly, Compound A was well tolerated by mice and was effective in inhibiting the growth of human triple-negative breast cancer and leukemia xenografts in vivo when administered intraperitoneally. Thus, exploiting oxidative vulnerabilities in cancer cells could be a selective and efficacious means to eradicate malignant cells as demonstrated by the curcumin analogs presented in this report with high therapeutic potential.