A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Synergistic effects of BKM120 and panobinostat on pre-B acute lymphoblastic cells: an emerging perspective for the simultaneous inhibition of PI3K and HDACs
Tekijät: Mahdieh Mehrpouri, Majid Momeny, Davood Bashash
Kustantaja: TAYLOR & FRANCIS LTD
Julkaisuvuosi: 2022
Journal: Journal of Receptors and Signal Transduction
Tietokannassa oleva lehden nimi: JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION
Lehden akronyymi: J RECEPT SIG TRANSD
Vuosikerta: 42
Numero: 1
Aloitussivu: 100
Lopetussivu: 108
Sivujen määrä: 9
ISSN: 1079-9893
eISSN: 1532-4281
DOI: https://doi.org/10.1080/10799893.2020.1853159
Tiivistelmä
The reputation of conventional treatment in acute lymphoblastic leukemia (ALL) has recently been questioned due to the considerable increment in the number of relapsed patients. The remarkable role of histone deacetylase (HDAC) enzymes in induction of chemo-resistance has provided an opportunity for HDAC inhibitors to be used as a treatment strategy in ALL; however, the compensatory activation of oncogenic pathways may negatively affect their promising effects. In the present study, we found an attenuating effect for PI3K axis on the anti-leukemic effects of panobinostat in pre-B ALL-derived Nalm-6 cells, as the harnessing of this pathway using BKM120 or CAL-101 resulted in a significant reduction in the number of viable cells as well as the metabolic activity. Moreover, we found the altered expression of p21, p27, c-Myc, and CDK4 upon co-treatment of the cells with panobinostat and BKM120, which was associated with a substantial blockage of cell cycle progression at G2/M phase. The companionship of the PI3K inhibitor with HDAC inhibitor also potentiated panobinostat-induced apoptotic cell death and enhanced the mRNA of Foxo3a and Foxo4. Conclusively, this study sheds light on the adjuvantive effects of BKM120 on panobinostat efficacy and outlined that the simultaneous inhibition of PI3K and HDACs may be a promising therapeutic approach to improve the cure rates of ALL.
The reputation of conventional treatment in acute lymphoblastic leukemia (ALL) has recently been questioned due to the considerable increment in the number of relapsed patients. The remarkable role of histone deacetylase (HDAC) enzymes in induction of chemo-resistance has provided an opportunity for HDAC inhibitors to be used as a treatment strategy in ALL; however, the compensatory activation of oncogenic pathways may negatively affect their promising effects. In the present study, we found an attenuating effect for PI3K axis on the anti-leukemic effects of panobinostat in pre-B ALL-derived Nalm-6 cells, as the harnessing of this pathway using BKM120 or CAL-101 resulted in a significant reduction in the number of viable cells as well as the metabolic activity. Moreover, we found the altered expression of p21, p27, c-Myc, and CDK4 upon co-treatment of the cells with panobinostat and BKM120, which was associated with a substantial blockage of cell cycle progression at G2/M phase. The companionship of the PI3K inhibitor with HDAC inhibitor also potentiated panobinostat-induced apoptotic cell death and enhanced the mRNA of Foxo3a and Foxo4. Conclusively, this study sheds light on the adjuvantive effects of BKM120 on panobinostat efficacy and outlined that the simultaneous inhibition of PI3K and HDACs may be a promising therapeutic approach to improve the cure rates of ALL.
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