Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines.
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.
Min
Dong-Joon
DJ
Division of Pediatric Hematology/Oncology, The Stephen D. Hassenfeld Children's Center for Cancer and Blood Diseases, New York University Cancer Institute, 317 East 34th Street, New York, NY 10016, USA.
Moskowitz
Naomi P
NP
Brownstein
Carrie
C
Lee
Hokyung
H
Horton
Terzah M
TM
Carroll
William L
WL
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D005047:Etoposide / Q000627:therapeutic use*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D053181:Caspase 8