Synergistic induction of apoptosis in B-cell chronic lymphocytic leukemia cells after treatment with all-trans retinoic acid in combination with interleukin-21 and rituximab.
OBJECTIVE
B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia in the Western world and characterized by the progressive expansion of malignant B lymphocytes in peripheral blood. In spite of advances in sciences to recognize the number of effective agents for the treatment of chronic lymphocytic leukemia (CLL), this leukemia is thought as incurable one. Introducing a new therapy that has a direct effect on B-CLL lymphocytes and no cytotoxic effects on the other cells is a great wish.


METHODS
Twenty-one patients with B-CLL were enrolled in the study. Peripheral blood mononuclear cells (PBMCs) were isolated from patients' blood samples and were further treated with all-tans retinoic acid (ATRA), interleukin (IL-21), and rituximab at concentrations of 30 ng/ml, 25 ng/ml, and 4 μg/ml, respectively. ATRA, IL21, and rituximab were used alone or in various combinations and their effects on apoptosis were measured using annexin V-fluorescein isothiocyanate apoptosis detection kit.


RESULTS
Treatment of the patients' cells with IL21 and rituximab showed a synergistic effect on the induction of apoptosis, in comparison with untreated CLL cells (P < 0.05). The induction of apoptosis by ATRA in combination with IL21 and rituximab were significantly increased compared to untreated CLL cells as a negative control (P < 0.01).


CONCLUSIONS
Treatment of patients' PBMCs by ATRA in combination with IL21 and rituximab and also IL21 in combination with rituximab showed synergistic induction of apoptosis compared to untreated CLL cells as a negative control (P < 0.01). It seems that ATRA in combination with IL21 and rituximab activate different pathways of apoptosis (extrinsic pathway, intrinsic pathway, and granzyme B pathway).
Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Kazem
K
Abbaszadeh-Goudarzi
Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Fazel
F
Shokri
Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Mostafa
M
Hosseini
Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Farhad
F
Jadidi-Niaragh
Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.
Ghasem
G
Ghalamfarsa
Department of Immunology, School of Public Health, Tehran University of Medical Sciences; Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
Ali Akbar
AA
Saboor-Yaraghi
D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers; D018956:CD5 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000069283:Rituximab / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000098546:Interleukin-21
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D015415:Biomarkers; D018956:CD5 Antigens; D007378:Interleukins; D000069283:Rituximab; D014212:Tretinoin; D000098546:Interleukin-21