Intracellular Localization Studies of the Luminescent Analogue of an Anticancer Ruthenium Iminophosphorane with High Efficacy in a Triple-Negative Breast Cancer Mouse Model.
Intracellular Localization Studies of the Luminescent Analogue of an Anticancer Ruthenium Iminophosphorane with High Efficacy in a Triple-Negative Breast Cancer Mouse Model.
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DOI：
10.1021/acs.inorgchem.1c02929
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发表时间：
2021-12-20
影响因子：
4.6
通讯作者：
Contel, Maria
中科院分区：
文献类型：
--
作者：
Miachin, Kirill;Del Solar, Virginia;El Khoury, Elsy;Nayeem, Nazia;Khrystenko, Anton;Appelt, Patricia;Neary, Michelle C.;Buccella, Daniela;Contel, Maria
经过二十多年的广泛研究，钌（II）化合物作为铂基临床抗癌药物的替代品的潜力已经被揭示出来。与顺铂相反，Ru（II）化合物具有不同的作用机制，不完全依赖于与DNA的相互作用。在我们小组之前的报告中，我们描述了阳离子，水溶性，有机金属钌（II）亚磷烷（IM）复合物的合成，表征和生物学评价，([(k - 6- p-cymene)Ru{（Ph3P=N-CO-2N-C5H4)-κ-N,O}Cl]Cl (1), Ru-IM）被发现对一组对顺铂耐药的细胞系具有高度的细胞毒性，包括三阴性乳腺癌MDA-MB-231，通过典型或caspase依赖性凋亡。在MDA-MB-231异种移植小鼠模型（治疗28天后）的研究中，肿瘤减少了56%，几乎可以忽略全身毒性，与其他器官相比，Ru肿瘤积累更有利。已知Ru-IM(1)仅与DNA弱相互作用，但其细胞内分布和最终目标仍不清楚。为了深入了解这种高效钌化合物的潜在机制，我们开发了两种发光类似物，其中含有BOPIPY荧光基团（或修饰）在亚磷磷烷支架中，其一般结构为[（η - 6-对伞花烃）Ru{(BODIPY-Ph2P=N-CO-2-N-C5H4)-κ- n,O}Cl]Cl （BODIPY-Ph2P: 48-（（4-二苯基膦）苯基）-4,4-二甲基-1,3,5,7-四甲基-2,6-二乙基-4-硼-3a，4 -二氮-s-茚二烯（3a））；和4,4-二氟-8-（4-（2-（4-（二苯基膦）-苯胺）乙基）氨甲基）苯基)-1,3,5,7-四甲基，2,6-二乙基，4-硼-3a，4 -二氮-s-茚二烯（3b）。我们报道了新化合物的合成、表征、亲脂性、稳定性、发光特性和在TNBC细胞系MDA-MB-231、非恶性乳腺细胞（MCF10A）和肺成纤维细胞（IMR-90）中的细胞活力研究。用荧光共聚焦显微镜对钌衍生物3b进行了研究。这些研究指出该化合物在内质网、线粒体和溶酶体中优先积累。ICP-OES分析还证实，Ru在细胞质部分（包括内质网和溶酶体）中积累较多，而在线粒体和细胞核中积累较少。ICP-OES分析表明母体化合物Ru-IM(1)优先在线粒体和细胞质中积累。线粒体和细胞质。随后的实验显示，Ru-IM(1)处理的MDA-MB-231细胞产生了显著的活性氧。
The potential of ruthenium (II) compounds as an alternative to platinum-based clinical anticancer agents has been unveiled after extensive research for over two decades. As opposed to cisplatin, Ru(II) compounds have distinct mechanisms of action that do not rely solely on interactions with DNA. In previous report from our group, we described the synthesis, characterization and biological evaluation of a cationic, water-soluble, organometallic ruthenium(II) iminophosphorane (IM) complex of p-cymene, ([(η6-p-Cymene)Ru{(Ph3P=N-CO-2N-C5H4)-κ-N,O}Cl]Cl (1), Ru-IM) that was found to be highly cytotoxic against a panel of cell lines resistant to cisplatin, including triple negative breast cancer MDA-MB-231, through canonical or caspase-dependent apoptosis. Studies on a MDA-MB-231 xenograft mice model (after 28 days of treatment) afforded an excellent tumor reduction of 56%, with almost negligible systemic toxicity, and a favored Ru tumor accumulation when compared to other organs. Ru-IM (1) is known to only interact weakly with DNA, but its intracellular distribution and ultimate targets remain unknown. To get an insight on potential mechanisms for this highly efficacious Ru compound, we have developed two luminescent analogues containing the BOPIPY fluorophore (or a modification) in the iminophosphorane scaffold with the general structure of [(η6-p-cymene)Ru{(BODIPY-Ph2P=N-CO-2-N-C5H4)-κ-N,O}Cl]Cl (BODIPY-Ph2P: 48-((4-Diphenylphosphino)phenyl)-4,4-dimethyl-1,3,5,7-tetramethyl-2,6-diethyl-4-bora-3a,4a-diaza-s-indacene (3a); and 4,4-difluoro-8-(4-((2-(4-(diphenylphosphino)-benzamido)ethyl)carbamoyl)phenyl)-1,3,5,7-tetramethyl,2,6-diethyl,4-bora-3a,4a-diaza-s-indacene (3b). We report on the synthesis, characterization, lipophilicity, stability, luminescence properties, and cell viability studies in the TNBC cell line MDA-MB-231, non-malignant breast cells (MCF10A) and lung fibroblasts (IMR-90) of the new compounds. Ruthenium derivative 3b was studied by fluorescence confocal microscopy. These studies point to a preferential accumulation of the compound in the endoplasmic reticulum, mitochondria and lysosomes. ICP-OES analysis also confirms a greater Ru accumulation in the cytoplasmic fraction, including ER and lysosomes, and a smaller percentage of accumulation in mitochondria and nucleus. ICP-OES analysis of the parent compound Ru-IM (1) indicates preferential mitochondrial and cytoplasmic accumulation. mitochondria and cytoplasm. Subsequent experiments in Ru-IM (1) treated MDA-MB-231 cells demonstrate significant reactive oxygen species generation.
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DOI：
10.1093/jnci/djv048
发表时间：
2015-06
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Kohler BA;Sherman RL;Howlader N;Jemal A;Ryerson AB;Henry KA;Boscoe FP;Cronin KA;Lake A;Noone AM;Henley SJ;Eheman CR;Anderson RN;Penberthy L
通讯作者：
Penberthy L
影响因子：
2.8
作者：
Aguilar, David;Bielsa, Raquel;Urriolabeitia, Esteban P.
通讯作者：
Urriolabeitia, Esteban P.
影响因子：
16.6
作者：
Davies, Laura H.;Stewart, Beverly;Harrington, Ross W.;Clegg, William;Higham, Lee J.
通讯作者：
Higham, Lee J.
影响因子：
3.6
作者：
BITTNER, S;ASSAF, Y;SMITH, CG
通讯作者：
SMITH, CG
影响因子：
2.2
作者：
Goncalves, Homero, Jr.;Guerra, Maximiliano Ribeiro;Bustamante Teixeira, Maria Teresa
通讯作者：
Bustamante Teixeira, Maria Teresa