Carnosol delays chemotherapy-induced DNA fragmentation and morphological changes associated with apoptosis in leukemic cells.
Carnosol, from the herb rosemary, has been shown to induce apoptotic cell death in high-risk pre-B acute lymphoblastic leukemia (ALL). In the present study, carnosol was tested for its ability to sensitize leukemia cells to chemotherapeutic agents. Carnosol reduced the percentage of cell death in the pre-B ALL lines SEM, RS4;11, and REH when combined with cytarabine, methotrexate, or vincristine compared to the chemotherapeutic agents alone. Analysis of DNA strand breaks by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling showed that carnosol delayed DNA cleavage in the cells when combined with chemotherapeutic drugs. Co-treatment of the cells with carnosol and chemotherapeutic drugs did not reduce mitochondrial membrane depolarization compared to the drug treatment alone. Time course analysis of caspase-3 activation by flow cytometry showed co-treatment with carnosol and drugs increased the activation of caspase-3 above that observed for the chemotherapeutic drugs alone. A lower percentage of caspase-3 positive cells progressed to an apoptotic phenotype when co-treated with carnosol and the chemotherapeutic drugs compared to drugs alone. These data show that carnosol blocks the terminal apoptotic events induced by chemotherapeutic drugs and suggest that increased dietary intake of carnosol may potentially decrease the effectiveness of some standard chemotherapy treatments used for leukemia.
Zunino
Susan J
SJ
United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, University of California, Davis 95616, USA. susan.zunino@ars.usda.gov
Storms
David H
DH
D045784:Abietanes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology
D045784:Abietanes; D000970:Antineoplastic Agents; C068623:carnosol; D053148:Caspase 3