Apoptosis of human T-cell acute lymphoblastic leukemia cells by diphenhydramine, an H1 histamine receptor antagonist.
Recently, it has been demonstrated that histamine plays an important role in the proliferation of normal and malignant cells. We have examined the effects of histamine, diphenhydramine, and cimetidine (H1 and H2 histamine receptor antagonists, respectively) on the in vitro proliferation of two human T-cell acute lymphoblastic leukemia cell lines, namely CCRF-CEM and Jurkat. Exogenous histamine did not alter the proliferation or viability of these cells. In contrast, diphenhydramine induced apoptosis in a dose- and time-dependent manner in both cell lines, whereas cimetidine failed to induce significant effects at similar concentrations. Diphenhydramine-induced apoptosis was evaluated in terms of morphology, flow cytometry, and the release of cytochrome c to the cytosol. The latter was partially mitigated by Bcl-2 overexpression. In human peripheral blood mononuclear cells, diphenhydramine inhibited cell proliferation without inducing apoptosis. Our findings indicate that endogenous histamine may be an important factor for the survival of CCRF-CEM, Jurkat, and peripheral blood mononuclear cells, and point to the potential application of H1 receptor antagonists as cytotoxic agents for the specific treatment of certain types of leukemia.
Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain.
Shawkat-Muhialdin
SM
Jangi
Aintzane
A
Asumendi
Jon
J
Arlucea
Naiara
N
Nieto
Gorka
G
Perez-Yarza
María C
MC
Morales
María
M
de la Fuente-Pinedo
María D
MD
Boyano
D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D004155:Diphenhydramine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D006634:Histamine H1 Antagonists; D004155:Diphenhydramine