Antitumoral synergism between a copper(II) complex and cisplatin improves in vitro and in vivo anticancer activity against melanoma, lung and breast cancer cells,Biochimica et Biophysica Acta (BBA) - General Subjects

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Antitumoral synergism between a copper(II) complex and cisplatin improves in vitro and in vivo anticancer activity against melanoma, lung and breast cancer cells
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2021-07-09 , DOI: 10.1016/j.bbagen.2021.129963
D Mariani ₁ , Z Ghasemishahrestani ₂ , W Freitas ₃ , P Pezzuto ₄ , A C Costa-da-Silva ₅ , A Tanuri ₄ , M M Kanashiro ₆ , C Fernandes ₇ , A Horn ₇ , M D Pereira ₂

Affiliation

Background

Intrinsic resistance of cancer cells is a major concern for the success of chemotherapy, and this undesirable feature stimulates further research into the design of new compounds and/or alternative multiple drug chemotherapy protocols.

Methods

In this study, we investigated the antitumoral potential of the coordination compounds [Cu(HPClNOL)Cl]Cl (1), [Fe(HPClNOL)Cl₂]NO₃ (2) and [Mn(HPClNOL)Cl₂] (3). Using the human, MCF-7 and A549, and the murine melanoma, B16-F10, cell lines, we determined the cytotoxicity, DCFH oxidation, disruption of mitochondrial membrane potential (ΔΨm), Sub-G1 and TUNEL positive cells, and caspase 8 and 9 activities. Fractional inhibitory concentration (FIC) and xenograft models were also assessed to evaluate the efficacy of antitumoral potential.

Results

We observed that only complex 1 was cytotoxic. The treatment of cancer cells with complex 1 triggered ROS generation and promoted the disruption of ΔΨm. Complex 1 increased the number of Sub-G1 and TUNEL positive cells, and the measurement of caspase 8 and 9 activity confirmed that apoptosis was triggered by the intrinsic pathway. FIC demonstrated that the combination of complex 1 with cisplatin was additive for the A549 cells whilst it was synergic for MCF-7 and B16-F10. Treatment with complex 1, either alone or combined with cisplatin, reduced tumor growth on xenograft models.

Conclusions

The present study brings new clues regarding the mechanism of action of [Cu(HPClNOL)Cl]Cl, either alone or in combination with cisplatin.

General significance

These results indicate that complex 1, administered either singly or in combination with current drugs, has real potential for use in cancer therapy.

中文翻译：

铜 (II) 复合物和顺铂之间的抗肿瘤协同作用可提高体外和体内对黑色素瘤、肺癌和乳腺癌细胞的抗癌活性

背景

癌细胞的内在抗性是化疗成功的一个主要问题，这种不受欢迎的特征刺激了对新化合物和/或替代多药化疗方案的设计的进一步研究。

方法

在本研究中，我们研究了配位化合物 [Cu(HPClNOL)Cl]Cl (1)、[Fe(HPClNOL)Cl ₂ ]NO ₃ (2)和 [Mn(HPClNOL)Cl ₂ ] (3 )的抗肿瘤潜力. 使用人 MCF-7 和 A549 以及鼠黑色素瘤 B16-F10 细胞系，我们确定了细胞毒性、DCFH 氧化、线粒体膜电位的破坏 (ΔΨm)、Sub-G1 和 TUNEL 阳性细胞以及半胱天冬酶 8和 9 项活动。还评估了分数抑制浓度 (FIC) 和异种移植模型，以评估抗肿瘤潜力的功效。

结果

我们观察到只有复合物1具有细胞毒性。用复合物1治疗癌细胞触发了 ROS 的产生并促进了 ΔΨm 的破坏。复合物1增加了 Sub-G1 和 TUNEL 阳性细胞的数量，caspase 8 和 9 活性的测量证实细胞凋亡是由内在途径触发的。FIC 证明复合物1与顺铂的组合对A549 细胞具有添加剂作用，同时对 MCF-7 和 B16-F10 具有协同作用。单独或与顺铂组合的复合物1治疗减少异种移植模型上的肿瘤生长。