Doxorubicin (Dox) is a widely neoplasm chemotherapeutic drug with high incidences of cardiotoxicity. Prodigiosin (PG), a red bacterial pigment from Serratia marcescens, has been demonstrated to potentiate Dox’s cytotoxicity against oral squamous cell carcinoma cells through elevating Dox influx and identified as a Dox enhancer via PG-induced autophagy; however, toxicity of normal cell remains unclear. This study is conducted to evaluate putative cytotoxicity features of PG/Dox synergism in the liver, kidney, and heart cells and further elucidate whether PG augmented Dox’s effect via modulating Dox metabolism in normal cells. Murine hepatocytes FL83B, cardio-myoblast h9c2, and human kidney epithelial cells HK-2 were sequentially treated with PG and Dox by measuring cell viability, cell death characteristics, oxidative stress, Dox flux, and Dox metabolism. PG could slightly significant increase Dox cytotoxicity in all tested normal cells whose toxic alteration was less than that of oral squamous carcinoma cells. The augmentation of Dox cytotoxicity might be attributed to the increase of Dox-mediated ROS accumulation that might cause slight reduction of Dox influx and reduction of Dox metabolism. It was noteworthy to notice that sustained cytotoxicity appeared in normal cells after PG and Dox were removed. Taken together, moderately metabolic reduction of Dox might be ascribed to the mechanism of increase Dox cytotoxicity in PG-induced normal cells; nevertheless, the determination of PG/Dox dose with sustained cytotoxicity in normal cells needs to be comprehensively considered.

阿霉素（Dox）是一种广泛的肿瘤化学治疗药物，具有很高的心脏毒性。Prodigiosin（PG），一种来自粘质沙雷氏菌的红色细菌色素已被证明可以通过增加Dox的流入来增强Dox对口腔鳞状细胞癌细胞的细胞毒性，并通过PG诱导的自噬被鉴定为Dox的增强剂；然而，正常细胞的毒性仍不清楚。进行这项研究以评估在肝脏，肾脏和心脏细胞中PG / Dox协同作用的假定细胞毒性特征，并进一步阐明PG是否通过调节正常细胞中的Dox代谢来增强Dox的作用。通过测量细胞活力，细胞死亡特征，氧化应激，Dox通量和Dox代谢，依次用PG和Dox处理鼠肝细胞FL83B，心肌成肌细胞h9c2和人肾上皮细胞HK-2。PG可能会在所有经测试的正常细胞（毒性变化小于口腔鳞状细胞癌细胞的毒性变化）中略微增加Dox细胞毒性。Dox细胞毒性的增加可能归因于Dox介导的ROS积累的增加，这可能会导致Dox内流的轻微减少和Dox代谢的减少。值得注意的是，去除PG和Dox后正常细胞中出现持续的细胞毒性。两者合计，Dox的适度代谢减少可能归因于PG诱导的正常细胞中Dox细胞毒性增加的机制。但是，需要综合考虑确定正常细胞中具有持续细胞毒性的PG / Dox剂量。值得注意的是，去除PG和Dox后正常细胞中出现持续的细胞毒性。两者合计，Dox的中等代谢减少可能归因于PG诱导的正常细胞中Dox细胞毒性增加的机制。但是，需要综合考虑确定正常细胞中具有持续细胞毒性的PG / Dox剂量。值得注意的是，去除PG和Dox后正常细胞中出现持续的细胞毒性。两者合计，Dox的中等代谢减少可能归因于PG诱导的正常细胞中Dox细胞毒性增加的机制。然而，需要综合考虑确定正常细胞中具有持续细胞毒性的PG / Dox剂量。