Ascorbic Acid Sensitizes Colorectal Carcinoma to the Cytotoxicity of Arsenic Trioxide via Promoting Reactive Oxygen Species-Dependent Apoptosis and Pyroptosis
Ascorbic Acid Sensitizes Colorectal Carcinoma to the Cytotoxicity of Arsenic Trioxide via Promoting Reactive Oxygen Species-Dependent Apoptosis and Pyroptosis
复制标题
抗坏血酸通过促进活性氧依赖性细胞凋亡和焦亡使结直肠癌对三氧化二砷的细胞毒性敏感
DOI：
10.3389/fphar.2020.00123
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发表时间：
2020-02-21
影响因子：
5.6
通讯作者：
Yang, Bao-Feng
中科院分区：
文献类型：
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作者：
Tian, Wei;Wang, Zhuo;Yang, Bao-Feng
三氧化二砷（ATO）是治疗急性早幼粒细胞白血病（APL）的有效药物，但其对结直肠癌（CRC）等实体瘤的抗肿瘤作用仍存在争议。抗坏血酸（AA）也产生针对肿瘤细胞的选择性细胞毒活性。在此，我们利用ATO/AA组合在产生对CRC细胞的细胞毒性方面的潜在益处，这可能为CRC的潜在组合化疗奠定基础。根据结果，我们发现ATO和AA以协同方式有效地抑制人CRC细胞的活力。AA和ATO共同激活caspase-3，引发细胞凋亡，上调caspase-1的表达，促进炎性小体的形成，诱导细胞凋亡。此外，活性氧（ROS）的过度产生的刺激被证明是由ATO/AA组合处理诱导的细胞凋亡和焦亡的亚细胞机制。我们的研究结果表明，ATO与常规剂量的AA组合提供了杀死CRC细胞的优势。ATO/AA组合的协同作用可能被认为是治疗CRC和可能的其他实体瘤的合理策略。
Arsenic trioxide (ATO) is an effective therapeutic agent against acute promyelocytic leukemia (APL); however, its anti-tumor effect on solid tumors such as colorectal cancer (CRC) is still in debate. Ascorbic acid (AA) also produces a selective cytotoxic activity against tumor cells. Here, we exploit the potential benefit of ATO/AA combination in generating cytotoxicity to CRC cells, which may lay the groundwork for the potential combinational chemotherapy of CRCs. According to the results, we found that ATO and AA effectively inhibited the viability of human CRC cells in a synergistic manner. AA and ATO corporately activated caspase-3 to trigger apoptosis and upregulated the expression of caspase-1 and promoted formation of inflammasomes to induce pyroptosis. Furthermore, the stimulation of reactive oxygen species (ROS) overproduction was demonstrated as a subcellular mechanism for apoptosis and pyroptosis induced by ATO/AA combination treatment. Our findings suggest that ATO combination with a conventional dosage of AA offers an advantage for killing CRC cells. The synergistic action of ATO/AA combination might be considered a plausible strategy for the treatment of CRC and perhaps other solid tumors as well.