Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones: differential cytotoxicity in healthy and cancer cells.
Safe and targeted anticancer efficacy of a novel class of antioxidant-conjugated difluorodiarylidenyl piperidones: differential cytotoxicity in healthy and cancer cells.
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DOI：
10.1016/j.freeradbiomed.2010.02.009
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发表时间：
2010-05-01
影响因子：
7.4
通讯作者：
Kuppusamy, Periannan
中科院分区：
文献类型：
--
作者：
Selvendiran, Karuppaiyah;Ahmed, Shabnam;Dayton, Alex;Kuppusamy, M. Lakshmi;Tazi, Mia;Bratasz, Anna;Tong, Liyue;Rivera, Brian K.;Kalai, Tamas;Hideg, Kalman;Kuppusamy, Periannan
开发能够选择性杀死癌细胞同时不伤害周围健康组织/细胞的智能抗癌药物对于安全有效的癌症治疗至关重要。我们报道了一类基于二亚芳基哌啶酮（DAP）与N-羟基吡咯啉（NOH，一种氮氧自由基前体）基团共轭的新型双功能化合物。我们假设DAP具有细胞毒性（抗癌）活性，而NOH部分将作为细胞毒性的组织特异性调节剂（抗氧化剂）发挥作用。该研究使用了四种DAP，即不含NOH的H-4073和H-4318以及具有NOH取代的HO-3867和HO-4200。该研究的目的是使用许多癌性（乳腺癌、结肠癌、头颈癌、肝癌、肺癌、卵巢癌和前列腺癌）和非癌性（平滑肌、主动脉内皮细胞和卵巢表面上皮细胞）人类细胞系来评估DAP的“概念验证”抗癌与抗氧化功效。使用基于MTT的细胞活力测定法测定细胞毒性。所有四种化合物均诱导癌细胞中细胞活力的显著丧失，而HO-3867和HO-4200在非癌细胞中显示出显著更低的细胞毒性。EPR测量结果表明，N-羟胺功能的代谢转化为氮氧自由基的代谢产物和超氧化物自由基清除（抗氧化剂）活性在非癌细胞相比，癌细胞中的显着更高的水平。Western-blot分析表明，DAP诱导的癌细胞生长停滞和凋亡是通过抑制STAT 3在Tyr 705和Ser 727残基的磷酸化和诱导凋亡标志物切割的caspase-3和PARP介导的。结果表明，抗氧化剂缀合的DAP将是有用的作为一种安全和有效的抗癌剂用于癌症治疗。
The development of smart anti-cancer drugs that can selectively kill cancer cells while sparing the surrounding healthy tissues/cells unharmed is of paramount importance for safe and effective cancer therapy. We report a novel class of bifunctional compounds based on diarylidenylpiperidone (DAP) conjugated with an N-hydroxypyrroline (NOH, a nitroxide precursor) group. We hypothesized that the DAP would have cytotoxic (anti-cancer) activity, while the NOH moiety would function as a tissue-specific modulator (anti-oxidant) of cytotoxicity. The study used four DAPs, namely H-4073 and H-4318 without NOH and HO-3867 and HO-4200 with NOH substitution. The goal of the study was to evaluate the ‘proof-of-concept’ anticancer-versus-antioxidant efficacy of the DAPs using a number of cancerous (breast, colon, head and neck, liver, lung, ovarian, and prostate cancer) and noncancerous (smooth muscle, aortic endothelial, and ovarian surface epithelial cells) human cell lines. Cytotoxicity was determined using an MTT-based cell viability assay. All four compounds induced significant loss of cell viability in cancer cells, while HO-3867 and HO-4200 showed significantly less cytotoxicity in noncancerous cells. EPR measurements showed a metabolic conversion of the N-hydroxylamine function to nitroxide with significantly higher levels of the metabolite and superoxide radical-scavenging (antioxidant) activity in noncancerous cells when compared to cancer cells. Western-blot analysis showed that the DAP-induced growth arrest and apoptosis in cancer cells were mediated by inhibition of STAT3 phosphorylation at Tyr705 and Ser727 residues and induction of apoptotic markers of cleaved caspase-3 and PARP. The results suggest that the antioxidant-conjugated DAPs will be useful as a safe and effective anticancer agent for cancer therapy.
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影响因子：
2.3
作者：
Adams, BK;Cai, JY;Shoji, M
通讯作者：
Shoji, M
影响因子：
3.5
作者：
Adams, BK;Ferstl, EM;Shoji, M
通讯作者：
Shoji, M
影响因子：
11.2
作者：
Li, Mao;Zhang, Zhuo;Zhang, Ruiwen
通讯作者：
Zhang, Ruiwen
影响因子：
--
作者：
Maliakel, Dani Mathew;Kagiya, Tsutomu V.;Nair, Cherupally Krishnan Krishnan
通讯作者：
Nair, Cherupally Krishnan Krishnan
影响因子：
20.3
作者：
Bharti, AC;Shishodia, S;Aggarwal, BB
通讯作者：
Aggarwal, BB