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Inhibition of Mcl-1 enhances Pevonedistat-triggered apoptosis in osteosarcoma cells.
- Source :
-
Experimental Cell Research . Sep2017, Vol. 358 Issue 2, p234-241. 8p. - Publication Year :
- 2017
-
Abstract
- Neddylation inhibitor Pevonedistat (MLN4924) is a novel anticancer drug and has demonstrated broad-spectrum anticancer activity. Nevertheless, we found that Pevonedistat had only a modest apoptotic effect in osteosarcoma (OS) cells. Moreover, we noted that inhibition of neddylation by Pevonedistat led to accumulation of Mcl-1 protein in OS cells. Because Mcl-1 is an important anti-apoptotic protein and also because apoptosis has been shown to be a major cell death pathway, we hypothesized that Mcl-1 accumulation negatively impacted Pevonedistat-mediated anticancer activity in OS cells. In this regard, we employed genetic or pharmacological approaches to inhibit Mcl-1 expression and to examine the effect on Pevonedistat-induced apoptosis in OS cells. We found that inhibition of Mcl-1 expression by siRNA considerably enhanced Pevonedistat-triggered the activation of caspase-3, PARP cleavage and apoptosis, and also dramatically promoted the ability of Pevonedistat to inhibit colony formation of OS cells. Moreover, we observed that flavopiridol, a FDA approved drug, inhibited Mcl-1 expression and substantially enhanced Pevonedistat-mediated activation of apoptosis signaling and significantly augmented cell killing effect in OS cells. Altogether, our study shows that Mcl-1 is a critical resistance factor to Pevonedistat monotherapy, and suggests that Pevonedistat in combinations with flavopiridol may achieve better anticancer therapy. [ABSTRACT FROM AUTHOR]
- Subjects :
- *MANTLE cell lymphoma
*APOPTOSIS
*OSTEOSARCOMA
*ANTINEOPLASTIC agents
*DRUG approval
Subjects
Details
- Language :
- English
- ISSN :
- 00144827
- Volume :
- 358
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Experimental Cell Research
- Publication Type :
- Academic Journal
- Accession number :
- 124877481
- Full Text :
- https://doi.org/10.1016/j.yexcr.2017.06.019