Novel vitamin D analogues; cytotoxic and anti-proliferative activity against a diffuse large B-cell lymphoma cell line and B-cells from healthy donors.
Calcitriol (1,25-dihydroxyvitamin D3, 1,25D3) and vitamin D side-chain modified analogs (VDAs) have gained considerable attention as potential drugs in the treatment of acute myeloid leukemia (AML), yet studies of the impact of 1,25D3and VDAs upon other haematological malignancies are more limited. To address this gap in knowledge, we have examined the action of 1,25D3and VDAs on a human cell line (DOHH2, K422) typifying diffuse large B-cell lymphoma (DLBCL) and also peripheral blood B-cells isolated from healthy donors. 1,25D3and certain VDAs displayed moderate cytotoxic and pro-apoptotic actions upon DLBCL cells. 1,25D3and VDAs (100nM) caused the death of approximately 40% DOHH2 cells after 24h stimulation, similar to their impact on HL-60 cells (acute myeloid leukaemia cell line). In addition, 1,25D3and VDAs displayed concentration and time-dependent anti-proliferative actions upon stimulated B-cells from healthy donors. The VDAs inhibited proliferation by approximately 30%. Hence VDAs may offer therapeutic potential for the treatment of DLBCL or conditions benefitted by B-cell depletion.
Celentyx Ltd., Birmingham Research Park, Birmingham B15 2SQ, UK; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK. Electronic address: pawel.kozielewicz@celentyx.com.
Paweł
P
Kozielewicz
Celentyx Ltd., Birmingham Research Park, Birmingham B15 2SQ, UK; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
Gillian
G
Grafton
Pharmaceutical Research Institute, Warsaw 01-793, Poland.
Andrzej
A
Kutner
Celentyx Ltd., Birmingham Research Park, Birmingham B15 2SQ, UK; School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
S John
SJ
Curnow
Celentyx Ltd., Birmingham Research Park, Birmingham B15 2SQ, UK.
John
J
Gordon
Celentyx Ltd., Birmingham Research Park, Birmingham B15 2SQ, UK; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, B15 2TT, UK.
Nicholas M
NM
Barnes
D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D018922:HL-60 Cells; D064368:Healthy Volunteers; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives*
D018941:Antigens, CD19; C000604811:CD19 molecule, human; D014807:Vitamin D; D002117:Calcitriol
B-cells; Diffuse large B-cell lymphoma; Drug synergy; Proliferation; Vitamin D analogues