p21^WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

Abstract

Keywords: childhood acute lymphoblastic leukemia, etoposide, p21 WAF1 , patient derived xenograft models, terameprocol, vorinostat p21 WAF1 is a well-characterized mediator of cell cycle arrest and may also modulate chemotherapy-induced cell death. The role of p21 WAF1 in drug-induced cell cycle arrest and apoptosis of acute lymphoblastic leukemia (ALL) cells was investigated using p53-functional patient-derived xenografts (PDXs), in which p21 WAF1 was epigenetically silenced in T-cell ALL (T-ALL), but not in B-cell precursor (BCP)-ALL PDXs. Upon exposure to diverse cytotoxic drugs, T-ALL PDX cells exhibited markedly increased caspase-3/7 activity and phosphatidylserine (PS) externalization on the plasma membrane compared with BCP-ALL cells. Despite dramatic differences in apoptotic characteristics between T-ALL and BCP-ALL PDXs, both ALL subtypes exhibited similar cell death kinetics and were equally sensitive to p53-inducing drugs in vitro, although T-ALL PDXs were significantly more sensitive to the histone deacetylase inhibitor vorinostat. Transient siRNA suppression of p21 WAF1 in the BCP-ALL 697 cell line resulted in a moderate depletion of the cell fraction in G1 phase and marked increase in PS externalization following exposure to etoposide. Furthermore, stable lentiviral p21 WAF1 silencing in the BCP-ALL Nalm-6 cell line accelerated PS externalization and cell death following exposure to etoposide and vorinostat, supporting previous findings. Finally, the Sp1 inhibitor, terameprocol, inhibited p21 WAF1 expression in Nalm-6 cells exposed to vorinostat and also partially augmented vorinostat-induced cell death. Taken together, these findings demonstrate that p21 WAF1 regulates the early stages of drug-induced apoptosis in ALL cells and significantly modulates their sensitivity to vorinostat.

Nanomicelles potentiate histone deacetylase inhibitor efficacy in vitro

“…SAHA treatment caused significant changes in proteins involved in both cell cycle and cell phenotype. We demonstrated that SAHA-loaded nanomicelles were able to up-regulate p21 and down-regulate p53 expression, consistent with the previous studies on the action of free SAHA on tumor growth inhibition by regulating the expression of these genes (Davies et al 2015;Ogata et al 2017). Detailed analysis of the effects of SAHA-loaded nanoparticles on EMT transition markers revealed a significant up-regulated E-cadherin expression, but with no affect N-cadherin expression.…”

Nanomicelles Potentiate HDAC Inhibitor Efficacy In Vitro.

“…Overexpression of p21 leads to the arrest of cells in the G1/G2 or S phases of the cell cycle [21,51], hence inhibiting the growth of tumor cells [52][53][54]. Here we demonstrated that SAHA-loaded nanomicelles were able to up-regulate p21 and down-regulate p53 expression, consistent with previous studies on the action of SAHA on tumor growth inhibition by regulating the expression of these genes [36,38,39,[55][56][57].…”

Nanomicelles potentiate histone deacetylase inhibitor efficacy in vitro.

“…At the molecular level SAHA treatment caused signi cant changes in proteins involved in both cell cycle and cell phenotype. We demonstrated that SAHA-loaded nanomicelles were able to up-regulate p21 and down-regulate p53 expression, consistent with previous studies on the action of free SAHA on tumor growth inhibition by regulating the expression of these genes (Davies et al 2015;Ogata et al 2017).…”