Resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression in NALM-6 cells.
Cytosine arabinoside (1-beta-D-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite used to induce remission in acute leukemia, but cellular resistance to Ara-C reflects a poor prognosis in cancer chemotherapy. To further investigate the mechanisms of resistance to Ara-C, we have established Ara-C-resistant NALM-6 cells. The activation of nuclear factor kappaB (NF-kappaB) was accompanied by the acquisition of Ara-C resistance. Telomerase activity has also increased with the acquisition of Ara-C resistance. The expression of Bid, Bax, or p53 proteins have been shown to increase correlated with the acquisition of Ara-C resistance. In contrast to the increase in these proteins, Bcl-2, Bcl-x, and Bag-1 proteins remained unchanged with the acquisition of Ara-C resistance. Fas expression increased with the acquisition of Ara-C resistance in the late stage. The induction of apoptosis and reduction of cell viability by cytotoxic anti-Fas antibody was more susceptible in resistant cells than parental cells. In conclusion, this report has shown that resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression.
Kanno
Syu-ichi
S
Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Japan. syu-kan@tohoku-pharm.ac.jp
Hiura
Takako
T
Shouji
Ai
A
Osanai
Yuu
Y
Ujibe
Mayuko
M
Ishikawa
Masaaki
M
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology* / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D005562:Formazans / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D005562:Formazans; D016328:NF-kappa B; D013778:Tetrazolium Salts; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D003561:Cytarabine; C079782:MTT formazan; D019098:Telomerase