The synthetic tubulysin derivative, tubugi-1, improves the innate immune response by macrophage polarization in addition to its direct cytotoxic effects in a murine melanoma model
2019
Аутори:
Drača, DijanaMijatović, Sanja
Krajnović, Tamara
Bogdanović Pristov, Jelena
Đukić, Tatjana
Kaluđerović, Goran N.
Wessjohann, Ludger A.
Maksimović-Ivanić, Danijela
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2019 Elsevier Inc.
Метаподаци
Приказ свих података о документуАпстракт:
Synthetic tubugis are equally potent but more stable than their natural forms. Their anticancer potential was estimated on a solid melanoma in vitro and in vivo. Tubugi-1 induced the apoptosis in B16 cells accompanied with strong intracellular production of reactive species, subsequently imposing glutathione and thiol group depletion. Paradoxically, membrane lipids were excluded from the cascade of intracellular oxidation, according to malondialdehyde decrease. Although morphologically apoptosis was typical, externalization of phosphatidylserine (PS) as an early apoptotic event was not detected. Even their exposition is pivotal for apoptotic cell eradication, primary macrophages successfully eliminated PS-deficient tubugi-1 induced apoptotic cells. The tumor volume in animals exposed to the drug in therapeutic mode was reduced in comparison to control as well as to paclitaxel-treated animals. Importantly, macrophages isolated from tubugi-1 treated animals possessed conserved phagocytic activity and were functionally and phenotypically recognized as M1. The cytotoxic effect of tubugi-1 is accomplished through its ability to polarize the macrophages toward M1, probably by PS independent apoptotic cell engulfment. The unique potential of tubugi-1 to prime the innate immune response through the induction of a specific pattern of tumor cell apoptosis can be of extraordinary importance from fundamental and applicable aspects.
Кључне речи:
Tubulysin; Cancer; Apoptosis; Macrophage polarization; PhosphatidylserineИзвор:
Experimental Cell Research, 2019, 380, 2, 159-170Финансирање / пројекти:
- Молекуларни механизми физиолошке и фармаколошке контроле инфламације и канцера (RS-MESTD-Basic Research (BR or ON)-173013)
- Leibniz Institute of Plant Biochemistry, Halle
- German Academic Exchange Service (DAAD)
URI
https://www.sciencedirect.com/science/article/pii/S0014482719302125?via%3Dihubhttps://radar.ibiss.bg.ac.rs/handle/123456789/3345