C-Myc inhibition sensitizes pre-B ALL cells to the anti-tumor effect of vincristine by altering apoptosis and autophagy: Proposing a probable mechanism of action for 10058-F4
Unlike the broad spectrum efficacies in wiping the malignant cells out, application of vincristine (VCR) in acute lymphoblastic leukemia (ALL) therapeutic protocol is partially restricted due to its high frequent resistant rate. Although several mechanisms have been enumerated for VCR resistance, to...
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Veröffentlicht in: | European journal of pharmacology 2020-03, Vol.870, p.172821-172821, Article 172821 |
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Zusammenfassung: | Unlike the broad spectrum efficacies in wiping the malignant cells out, application of vincristine (VCR) in acute lymphoblastic leukemia (ALL) therapeutic protocol is partially restricted due to its high frequent resistant rate. Although several mechanisms have been enumerated for VCR resistance, to the best of our knowledge, there is no report reflecting the suppressive effect of oncogenic pathways on VCR cytotoxicity in ALL. The results of the present study indicated that both pre-B ALL-derived REH and Nalm-6 cells were partly resistant to VCR, with this note that Nalm-6 cells displayed more resistant phenotype. More interestingly, we showed for the first time that among inhibitors of different signaling pathways including those targeting PI3K, ERK, and NF-κB, the enhancive effect of small molecule inhibitor of c-Myc 10058-F4 was more significant on VCR cytotoxicity. Inhibition of c-Myc in VCR-treated Nalm-6 cells promoted a caspase-3-dependent apoptosis not only through altering the balance between death promoters to death suppressors, but also via modulating the expression of autophagy-related genes. Noteworthy, favorable impact of 10058-F4 on VCR anti-leukemic effect was not restricted to the induction of cell death and this agent also reinforced VCR anti-proliferative effect through disturbing cell cycle progression and hampering the expression of Pin1 and hTERT. In conclusion, it seems that targeting c-Myc could produce a synergistic anti-cancer effect with VCR and provide a fundamental infrastructure for a promising approach in ALL. |
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ISSN: | 0014-2999 1879-0712 |
DOI: | 10.1016/j.ejphar.2019.172821 |