The anti‐apoptotic genes Bcl‐X_L and Bcl‐2 are over‐expressed and contribute to chemoresistance of non‐proliferating leukaemic CD34⁺ cells

Abstract

Summary. In acute myeloid leukaemia (AML), cell kinetic quiescence has been postulated to contribute to drug resistance. As the anti-apoptotic genes Bcl-2 and Bcl-X L have been implicated in cell cycle regulation, we investigated the expression of these genes in non-proliferating (Q) and proliferating (P) AML and normal CD34 + progenitor cells. Using reverse transcription polymerase chain reaction, Bcl-X L and Bcl-2 were overexpressed in Q versus P AML cells, whereas no difference in Bcl-X S and Bax expression was found. Furthermore, the Bcl-X L /X S but not the Bcl-2/Bax ratio was higher in Q AML compared with normal CD34 + Q cells (P ¼ 0AE001). An inverse correlation between Bcl-2 expression of leukaemic Q cells and their ability to enter the cell cycle was found. Treatment with all-trans retinoic acid (ATRA) reduced Bcl-2 and Bcl-X L expression in the leukaemic Q cells, and enhanced their chemosensitivity to cytosine arabinoside (ara-C). These findings demonstrate overexpression of the anti-apoptotic proteins Bcl-X L and Bcl-2 in quiescent CD34+ AML cells and suggest their involvement in the chemoresistance. The observed inverse correlation between Bcl-2 and proliferation suggests a role for Bcl-2 in the cell cycle regulation of AML. These findings could be used in the development of therapies that selectively induce apoptosis in quiescent leukaemic progenitor cells.

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

“…This result is in line with a previously described balance between anti-and pro-apoptotic proteins directly regulating MMP and chemoresistance. 15,[19][20][21][22] However, these observations did not unravel the pathways upstream of MMP, which can be involved in the development of CDDP resistance. It has been previously established that ER homeostasis can be a common extra-nuclear target of CDDP.…”

Concomitant Inhibition of MDM2 and Bcl-2 Protein Function Synergistically Induce Mitochondrial Apoptosis in AML

“…Our findings suggest that Mdm2 and Bcl-2 inhibitors can synergistically induce apoptosis in AML cells independent of cell cycle phase, even though the cytotoxicity of each agent alone is cell cycle dependent. Since Bcl-2 is overexpressed in AML and Bcl-2 overexpression or an increased Bcl-2/Bax ratio is associated with poor clinical response, [18][19][20]47 the targeted combination therapy proposed here would constitute a mechanism-based therapy with considerable clinical potential.…”

Nonlinear simulation of the effect of microenvironment on tumor growth

“…In future work, we shall explicitly model the quiescent tumor cell population, as these cells are particularly important when considering the efficacy of therapy (Konopleva et al, 2002;Ravandi and Estrov, 2006).…”