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钯(II)希夫碱配合物在早期使细胞周期停滞,诱导细胞凋亡,减少艾氏腹水瘤负担:肿瘤治疗的新候选药物。

Palladium(II) Schiff base complex arrests cell cycle at early stages, induces apoptosis, and reduces Ehrlich solid tumor burden: a new candidate for tumor therapy.

机构信息

Chemistry Department, Faculty of Science, Damietta University, Damietta, 34517, Egypt.

Chemistry Department, Faculty of Technology and Education, Beni-Suef University, Beni-Suef, Egypt.

出版信息

Invest New Drugs. 2022 Aug;40(4):681-689. doi: 10.1007/s10637-022-01234-6. Epub 2022 Mar 30.

Abstract

Although many cancer drugs are clinically approved, they still suffer from no adequate efficiency or drug resistance, or bad side effects. Therefore, developing safer alternatives of competitive efficiency is needed. This study aimed to investigate, for the first time, the antitumor and apoptotic activities of palladium(II) 2-hydroxyimino-3-(2-hydrazonopyridyl)-butane complex against Ehrlich carcinoma. In vitro, EAC cells were incubated with the complex, and the cells' viability, caspase 8 activity, and cell cycle changes were evaluated. In vivo, eighty adult female Swiss albino mice were distributed randomly in the following groups (n = 10): Normal, EAC, EAC + Cisplatin, and four groups EAC + Complex as well as Normal + Complex. Bodyweight changes were noted. On day 22 mice were sacrificed. Tumors' volume and weight were recorded. Blood picture was routinely investigated. The median survival time (MST) and percent increase in life span (%ILS) were monitored. In vitro, the complex reduced the %viable EAC cells, increased caspase 8 activity, arrested cell cycle at G0/G1, and reduced G2(M) population indicating antiproliferative and antitumor activities via inducing apoptosis. Treatment with the complex in a dose-dependent mode significantly decreased tumor volume and weight, extended the MST and the %ILS, increased mice body weight gain, and improved the blood indexes. Treatment of EAC-bearing mice with the complex highest dose showed more desirable outcomes than treatment with cisplatin. The Normal + Complex group showed no pathological changes indicating safety. In conclusion, our outcomes recommend the Pd(II) complex as a new optimistic candidate for tumor therapy after further studies for validation.

摘要

尽管许多癌症药物已在临床上获得批准,但它们仍然存在疗效不足、耐药性或副作用大等问题。因此,需要开发更安全、疗效相当的替代品。本研究首次探讨了钯(II)2-羟亚氨基-3-(2-酰肼吡啶基)-丁烷配合物对艾氏腹水癌的抗肿瘤和促凋亡活性。体外,用该配合物孵育 EAC 细胞,评估细胞活力、半胱天冬酶 8 活性和细胞周期变化。体内,将 80 只成年雌性瑞士白化病小鼠随机分为以下几组(n=10):正常组、EAC 组、EAC+Cisplatin 组和 4 个 EAC+Complex 组以及正常+Complex 组。记录体重变化。第 22 天处死小鼠。记录肿瘤体积和重量。常规检查血象。监测中位生存时间(MST)和寿命延长百分率(%ILS)。体外,该配合物降低了 EAC 细胞的存活率,增加了半胱天冬酶 8 的活性,使细胞周期停滞在 G0/G1 期,减少了 G2(M)期细胞群,表明通过诱导细胞凋亡具有抗增殖和抗肿瘤活性。以剂量依赖的方式用该配合物治疗显著降低了肿瘤体积和重量,延长了 MST 和 %ILS,增加了小鼠体重增加,并改善了血液指标。用该配合物的最高剂量治疗 EAC 荷瘤小鼠的效果优于用顺铂治疗。正常+Complex 组未显示出病理变化,表明安全性。总之,我们的结果表明,在进一步研究验证后,该 Pd(II)配合物有望成为肿瘤治疗的新候选药物。

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