Abstract
The riboside derivative acadesine (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) is currently being tested in clinical trials as a promising anti-tumor drug. Intracellular target of acadesine is adenosine monophosphate-activated protein kinase (АМРК), an important regulatory molecule of energy metabolism. It is expected that acadesine would be active in tumors under hypoxia conditions. In normoxia (cells incubated in 21 % oxygen), acadesine inhibited proliferation and induced cell death of breast adenocarcinoma, including the triple negative breast cancer line. When oxygen partial pressure was decreased to 1 % (experimental hypoxia), acadesine inhibited activation of reporter construct responsive to HIF-1α (hypoxia inducible factor 1 alpha) transcription factor. This effect was observed for acadesine in concentrations close to cytotoxic. Acadesine retained cytotoxicity under hypoxia and decreased the survival of the MDA-MB-231 cell line when used in combination with cisplatin. These results considerably widen acadesine’s field of application and allow to assume its efficacy in chemotherapy combination regimens for breast cancer, including the tumors with low oxygenation.
Highlights
Производное рибозида акадезин (5‐аминоимидазол-4‐карбоксамид-1‐β-D-рибофуранозид) проходит клинические испытания как перспективный противоопухолевый препарат
It is expected that acadesine would be active in tumors under hypoxia conditions
In normoxia, acadesine inhibited proliferation and induced cell death of breast adenocarcinoma, including the triple negative breast cancer line
Summary
Производное рибозида акадезин (5‐аминоимидазол-4‐карбоксамид-1‐β-D-рибофуранозид) проходит клинические испытания как перспективный противоопухолевый препарат. Действие акадезина на клетки рака молочной железы в условиях гипоксии В нормоксии (инкубация клеток в атмосфере с 21 % кислорода) акадезин вызывал торможение пролиферации и гибель клеток аденокарциномы молочной железы, в том числе линии трижды негативного рака. Акадезин сохранял цитотоксичность в условиях гипоксии и снижал обусловленную гипоксией устойчивость клеток линии MDA-MB-231 к действию цисплатина.
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