Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Iran.
J Appl Microbiol. 2018 Oct;125(4):1017-1029. doi: 10.1111/jam.13949. Epub 2018 Jul 18.
Matrix metalloproteinase-9 (MMP-9) and survivin are involved in several steps of carcinogenesis in acute lymphoblastic leukaemia (ALL). Yet, no MMP-9 and survivin-modulating drugs with low toxicity on normal cells but high efficacy against high MMP-9- and survivin-expressing leukaemia cells have been approved for clinical application in ALL. Prodigiosin, a secondary metabolite of Serratia marcescens, induces apoptosis in different kinds of cancer cells with low toxicity on normal cells. However, little is known about the effects of this compound on the high MMP-9- and survivin-expressing leukaemia cells.
CCRF-CEM cells as a model for high MMP-9- and survivin-expressing ALL cells were treated with 100, 200 and 400 nmol l prodigiosin after which cell number, proliferation rate, MMP-9 and survivin expression, caspase-3 activation and apoptosis were evaluated. After 24-, 48-, and 72-h treatments with 100, 200 and 400 nmol l prodigiosin, proliferation rates were measured to be 92·3-76·7%, 82-63% and 63·7-46·6% respectively. Treatment with prodigiosin for 48 h decreased MMP-9 mRNA levels followed by decreases in secreted (S) and intracellular (I) MMP-9 protein levels by 20-22% and 69-72% for 100-400 nmol l prodigiosin respectively. Prodigiosin decreased survivin protein levels from 40 to 26% followed by 3·7-5·6-fold increases in caspase-3 activation for the aforementioned prodigiosin concentration ranges. Treatment with 100-400 nmol l prodigiosin increased the caspase-3/survivin, caspase-3/I-MMP-9 and caspase-3/S-MMP-9 ratios by 6-7·3-, 11·5-19·1- and 4·9-6·8-fold increases respectively. A dramatic increase in the number of apoptotic cells was also observed with increasing prodigiosin concentrations.
The inhibitory effects of prodigiosin on MMP-9 and survivin expression, as well as its pro-apoptotic capacity, represent a novel therapeutic avenue against ALL cells.
These findings provide an important and interesting basis to develop a new therapeutic compound with high potential against ALL cells.
基质金属蛋白酶-9（MMP-9）和存活素参与急性淋巴细胞白血病（ALL）的多个致癌步骤。然而，目前还没有批准用于 ALL 临床应用的、对正常细胞毒性低但对高 MMP-9 和存活素表达的白血病细胞具有高疗效的 MMP-9 和存活素调节药物。灵菌红素是粘质沙雷氏菌的一种次生代谢产物，可诱导多种癌细胞凋亡，对正常细胞毒性低。然而，人们对这种化合物对高 MMP-9 和存活素表达的白血病细胞的影响知之甚少。
用 100、200 和 400 nmol l 灵菌红素处理 CCRF-CEM 细胞作为高 MMP-9 和存活素表达 ALL 细胞模型，评估细胞数量、增殖率、MMP-9 和存活素表达、半胱天冬酶-3 激活和细胞凋亡。用 100、200 和 400 nmol l 灵菌红素处理 24、48 和 72 h 后，增殖率分别为 92.3-76.7%、82-63%和 63.7-46.6%。灵菌红素处理 48 h 后 MMP-9 mRNA 水平降低，随后 S 和 I 型 MMP-9 蛋白水平分别降低 20-22%和 69-72%，浓度范围为 100-400 nmol l。灵菌红素使存活素蛋白水平从 40%降低至 26%，随后 caspase-3 激活增加 3.7-5.6 倍，上述灵菌红素浓度范围相同。用 100-400 nmol l 灵菌红素处理可使 caspase-3/存活素、caspase-3/I-MMP-9 和 caspase-3/S-MMP-9 比值分别增加 6-7.3、11.5-19.1-和 4.9-6.8 倍。随着灵菌红素浓度的增加，凋亡细胞数量也显著增加。
灵菌红素对 MMP-9 和存活素表达的抑制作用及其促凋亡能力为 ALL 细胞提供了一种新的治疗途径。
这些发现为开发一种针对 ALL 细胞具有高潜力的新型治疗化合物提供了重要而有趣的基础。
