Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method
Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method
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DOI：
10.1016/j.ejphar.2021.173919
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发表时间：
2021-02-22
影响因子：
5
通讯作者：
Banerjee, Aditi
中科院分区：
文献类型：
--
作者：
Banerjee, Vivekjyoti;Sharda, Neha;Banerjee, Aditi
由于新的和改进的治疗方案，结直肠癌（CRC）死亡率已经下降了几十年。然而，CRC仍然是美国第三大诊断癌症。因此，需要一种新的治疗方法来克服Colospheroids抑制和耐药性。据文献记载，穿心莲（AGP）和褪黑激素（MLT）具有抗癌特性。我们的目标是评估它们对转移性结肠癌细胞（mCRC）和colospheroid的协同作用。用系列稀释的AGP和MLT同时处理HT-29和HCT-15 mCRC细胞24、48和72 h。使用MTT测定法监测细胞活力。Chou-Talalay联合用药法以中位效应方程为基础，为联合指数和等效线方程提供了理论依据。这允许使用CompuSyn软件定量测定药物相互作用，其中CI < 1、= 1和>1分别表示协同、相加和拮抗作用。我们的结果表明，AGP和MLT组合显示协同作用，HT-29和HCT-15的CI值分别为0.35293和0.34152，Fa = 0.50-0.90的抑制分数，如Fa-CI图和等效线图所示。在基于形态学、活力和集落形成的类球体（HT-29-s和HCT-15-s）中以及在5-FU耐药细胞（HT-29 R和HCT-116 R）活力中验证了协同作用值。细胞活力降低的机制是由于ER应激蛋白的诱导和血管生成抑制。我们的结果为AGP联合MLT治疗mCRC提供了依据。
Colorectal cancer (CRC) mortality has diminished for decades due to new and improved treatment profiles. However, CRC still ranks as the third most diagnosed cancer in the US. Therefore, a new therapeutic approach is needed to overcome colospheroids inhibition and drug resistance. It is well documented that andrographolide (AGP) and melatonin (MLT) have anti-carcinogenic properties. Our goal was to evaluate their synergistic effects on metastatic colon cancer cells (mCRC) and colospheroids. HT-29 and HCT-15 mCRC cells were simultaneously treated with serial dilutions of AGP and MLT for 24, 48 and 72 h. Cell viability was monitored using the MTT assay. The Chou-Talalay method for drug combination is based on the median effect equation, providing a theoretical basis for the combination index and the isobologram equation. This allows quantitative determination of drug interactions using the CompuSyn software, where CI < 1, = 1, and >1 indicates synergistic, additive, and antagonistic effects respectively. Our results demonstrate that AGP and MLT in combination show synergism with CI values of 0.35293 and 0.34152 for HT-29 and HCT-15 respectively and a fractional inhibition of Fa = 0.50-0.90, as shown by the Fa-CI plot and isobologram. The synergism value was validated in colospheroids (HT-29-s and HCT-15-s) based on morphology, viability, and colony formation and in 5-FU drug resistant cell (HT-29R and HCT-116R) viability. The mechanism(s) of decreased cell viability are due to the induction of ER stress proteins and angiogenic inhibition. Our results provide rationale for using AGP in combination with MLT on mCRC.