Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines

Abstract

Cancer cell resistance to chemotherapy may be mediated by defects in apoptotic pathways. A prior study showed that in vivo apoptosis of Acute Lymphoblastic Leukemia (ALL) blasts in response to chemotherapy could occur through diverse pathways including both p53-dependent and -independent mechanisms. In this study we investigated the apoptotic response in more detail by using a panel of ALL cell lines that differed in respect to p53 status. Upon exposure to a uniform stimulus, expression of apoptotic proteins, including the effector caspase-3, varied among ALL cell lines partly depending on p53 transcriptional activity and caspase-8 activation. Although the expression and contribution to apoptosis differed among known members of the apoptotic pathway, apoptosis was universally mediated by mitochondrial depolarization. The NFkappaB pathway was activated in response to chemotherapy but NFkappaB inhibition appeared to not influence chemosensitivity. This study further documents the highly variable nature of cell death programs in ALL and provides the foundation for cell death pathway modulation to improve ALL cure rates without increasing chemotherapy-related toxicity.

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

“…These observations are consistent with the finding that NF-kB signaling is indispensable for the homeostasis of mature B cells and contributes to the survival of mature B-cell malignancies (17,18). The significance of NF-kB signaling for the survival and differentiation of precursor B cells is still less clear (17,19), and its role in the leukemogenesis and treatment response of BCP-ALL remains controversial (20)(21)(22).…”

“…In contrast, new findings (35-37) and our results indicate that NF-kB has also a tumor-suppressive function. In ALLs, a constitutive activation of NF-kB as a survival factor but also an involvement of NF-kB signaling in chemotherapy-induced apoptosis was reported (20,37,38). A clear correlation between NF-kB expression and BCP-ALL pathophysiology remains to be established.…”

p53-independent Epigenetic Repression of the p21WAF1 Gene in T-cell Acute Lymphoblastic Leukemia

“…Moreover, reduced basal levels of p21 WAF1 mRNA and protein in T-ALL versus BCP-ALL were demonstrated in independent cohorts of patients on separate continents, which strengthens the validity of our observations. The down-regulation of p21 WAF1 has been previously highlighted in T-ALL cell lines (18,26,48) and primary cells (49), although a mechanistic explanation of this phenomenon has yet to be presented.…”

Bystander killing of malignant cells via the delivery of engineered thymidine-active deoxycytidine kinase for suicide gene therapy of cancer

“…However, tumor cells are highly heterogeneous with respect to their sensitivity towards most chemotherapeutic agents. 1,2 Therefore, enhancing chemotherapy via the delivery of specific 'suicide' genes, which potentiate the rapid activation of select chemotherapeutic agents, has been explored for the treatment of solid tumors. 3 --5 The targeted or localized delivery of 'suicide' genes into tumor cells not only greatly augments their sensitivity to select prodrugs, but also avoids the peripheral toxicity common to the use of those chemotherapeutic agents.…”