空泡化
MCF-7型
程序性细胞死亡
细胞凋亡
自噬
癌细胞
化学
细胞生物学
二硫仑
坏死性下垂
液泡
线粒体
癌症研究
生物化学
药理学
癌症
生物
细胞质
内分泌学
遗传学
人体乳房
作者
Marina Solovieva,Yuri Shatalin,Irina Odinokova,Olga Krestinina,Yulia Baburina,Artem Mishukov,Yana Lomovskaya,Liubov Pavlik,Irina Mikheeva,Ekhson Holmuhamedov,Vladimir Akatov
标识
DOI:10.1016/j.bbagen.2022.130184
摘要
Dithiocarbamates and derivatives (including disulfiram, DSF) are currently investigated as antineoplastic agents. We have revealed earlier the ability of hydroxocobalamin (vitamin В12b) combined with diethyldithiocarbamate (DDC) to catalyze the formation of highly cytotoxic oxidized derivatives of DSF (DSFoxy, sulfones and sulfoxides).Electron and fluorescent confocal microscopy, molecular biology and conventional biochemical techniques were used to study the morphological and functional responses of MCF-7 human breast cancer cells to treatment with DDC and B12b alone or in combination.DDC induces unfolded protein response in MCF-7 cells. The combined use of DDC and B12b causes MCF-7 cell death. Electron microscopy revealed the separation of ER and nuclear membranes, leading to the formation of both cytoplasmic and perinuclear vacuoles, with many fibers inside. The process of vacuolization coincided with the appearance of ER stress markers, a marked damage to mitochondria, a significant inhibition of 20S proteasome, and actin depolimerization at later stages. Specific inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis did not prevent cell death. A short- time (6-h) exposure to DSFoxy caused a significant increase in the number of entotic cells.These observations indicate that MCF-7 cells treated with a mixture of DDC and B12b die by the mechanism of paraptosis. A short- time exposure to DSFoxy caused, along with paraptosis, a significant activation of the entosis and its final stage, lysosomal cell death.The results obtained open up opportunities for the development of new approaches to induce non-apoptotic death of cancer cells by dithiocarbamates.
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