Background

Cisplatin (CIS) is widely applied as an anticancer drug for various cancer types, including liver, breast, colorectal, and pancreatic cancers; however, its usage is limited due to side effects.

Objective

We investigated whether combined therapy of Graviola (Annona muricata) leaves extract (GLE) and CIS could reduce CIS doses without decreasing its anticancer potential.

Methods

The MCF7, HepG2, CaCo2, or PANC1 cells were divided into four groups for each cell line as follows: group1 (G1): untreated cells, G2: cells treated with GLE, G3: cells treated with CIS, and G4: cells treated with GLE, after 2 h treated with CIS. All combinations were prepared as non-constant ratio from GLE. The cytotoxicity, gene expression, cell cycle arrest were determined by MTT assay, real-time PCR, and cell flow cytometry, respectively.

Results

Treatment with GLE and/or CIS-induced cytotoxic effect on HepG2, MCF7, CaCo2, and PANC1 cancer cells with the best effect of combined therapy. All twelve non-constant ratio combinations (GLE + CIS) for each cell line resulted in a significant higher cytotoxic effect than single drug treatment. The combination index (CI) values for all combinations were less than one, indicating the presence of synergistic cytotoxic effect between CIS and GLE against the four cancer cell lines. This anticancer effect was triggered through mitochondrial-dependent apoptosis with the downregulation of caspase3, Bax, and p53 and upregulation of Bcl2. GLE also shifted G0/G1 phase of cell cycle arrest induced by CIS to S and G2/M phases. Interestingly, this combined therapy did not affect oxidative stress (indicated by higher malondialdehyde level and lower activities of SOD, CAT, and GPX) induced by CIS; however, it downregulated the expression of MAPK1 and multidrug resistance gene MDR1.

Conclusion

These results demonstrate that Graviola leaves extract optimizes the antitumor potential of cisplatin and could be utilized as a natural adjuvant to decrease cisplatin side effects.

中文翻译：

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鼠尾草叶提取物增强顺铂对多种癌细胞的抗癌作用

背景

顺铂（CIS）被广泛用作各种癌症的抗癌药物，包括肝癌，乳腺癌，结直肠癌和胰腺癌。但是，由于副作用，其使用受到限制。

目的

我们调查了Graviola（Annona muricata）叶提取物（GLE）和CIS的联合治疗是否可以降低CIS剂量而不降低其抗癌潜力。

方法

对于每个细胞系，将MCF7，HepG2，CaCo2或PANC1细胞分为四组：第1组（G1）：未处理的细胞； G2：经GLE处理的细胞； G3：经CIS处理的细胞；以及G4：经GLE处理的细胞GLE，用CIS治疗2小时后。所有组合均由GLE制成非恒定比例。通过MTT测定，实时PCR和细胞流式细胞术分别测定细胞毒性，基因表达，细胞周期停滞。

结果

用GLE和/或CIS诱导的对HepG2，MCF7，CaCo2和PANC1癌细胞的细胞毒性作用具有最佳联合治疗效果。每个细胞系的所有十二种非恒定比例组合（GLE + CIS）导致的细胞毒性作用明显高于单一药物治疗。所有组合的组合指数（CI）值均小于1，表明CIS和GLE之间对四种癌细胞系存在协同的细胞毒性作用。这种抗癌作用是通过线粒体依赖性细胞凋亡与caspase3，Bax和p53的下调以及Bcl2的上调触发的。GLE还将CIS诱导的细胞周期停滞的G0 / G1期转移到S和G2 / M期。有趣的是，这种联合疗法并未影响CIS诱导的氧化应激（以丙二醛水平较高和SOD，CAT和GPX活性较低表示）。然而，它下调了MAPK1和多药耐药基因MDR1的表达。

结论

这些结果表明，Graviola叶片提取物可优化顺铂的抗​​肿瘤潜力，并可作为天然佐剂来减少顺铂的副作用。