Papież Monika A, Krzyściak Wirginia, Szade Krzysztof, Bukowska-Straková Karolina, Kozakowska Magdalena, Hajduk Karolina, Bystrowska Beata, Dulak Jozef, Jozkowicz Alicja
Department of Cytobiology, Jagiellonian University Medical College, Krakow, Poland.
Department of Medical Diagnostic, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
Drug Des Devel Ther. 2016 Feb 4;10:557-70. doi: 10.2147/DDDT.S92687. eCollection 2016.
Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.
姜黄素可能对自由基水平升高的肿瘤细胞产生更具选择性的细胞毒性作用。在此，我们研究了姜黄素是否能调节依托泊苷在髓系白血病细胞和造血来源的正常细胞中的作用。将HL-60细胞系、正常髓系祖细胞分化簇（CD）-34(+)细胞和粒细胞在不同浓度的姜黄素和/或依托泊苷中孵育4或24小时。使用患有急性髓系白血病的棕色挪威大鼠（BNML）来证明姜黄素在体内对依托泊苷作用的影响。大鼠用姜黄素治疗23天，依托泊苷在实验的最后3天给药。姜黄素协同增强了依托泊苷的细胞毒性作用，并增强了这种细胞抑制药物在白血病HL-60细胞中诱导的组蛋白H2AX的凋亡和磷酸化。相比之下，姜黄素在正常CD34(+)细胞和粒细胞中并未显著改变依托泊苷诱导的细胞毒性和H2AX磷酸化。姜黄素通过增强自由基产生来改变依托泊苷在HL-60细胞中的细胞毒性作用，因为用N-乙酰-L-半胱氨酸（NAC）预孵育可显著降低姜黄素本身以及两种化合物组合的细胞毒性作用。相比之下，NAC并未降低依托泊苷的细胞毒性作用。因此，在HL-60细胞中，氧化应激在姜黄素的细胞毒性作用中比在依托泊苷的细胞毒性作用中发挥更大的作用。体外实验结果在BNML模型中得到证实。姜黄素预处理增强了依托泊苷在BNML大鼠中的抗白血病活性（肿瘤缩小程度是单独使用依托泊苷的1.57倍；P<0.05），并且比单独使用依托泊苷更有效地诱导BNML细胞凋亡（与单独使用依托泊苷相比变化倍数为1.54倍；P<0.05），但这种治疗可保护非白血病B细胞免于凋亡。因此，姜黄素可通过敏感髓系白血病细胞中的活性氧增加依托泊苷的抗白血病作用，并且对正常人类细胞无害。
