Resveratrol increases rate of apoptosis caused by purine analogues in malignant lymphocytes of chronic lymphocytic leukemia.
In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (γH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in γH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis.
Podhorecka
Monika
M
Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Staszica 11, 20-081, Lublin, Poland. monika.podhorecka@am.lublin.pl
Halicka
Dorota
D
Klimek
Piotr
P
Kowal
Malgorzata
M
Chocholska
Sylwia
S
Dmoszynska
Anna
A
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D017338:Cladribine / Q000494:pharmacology / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D006657:Histones / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011687:Purines / Q000737:chemistry; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D013267:Stilbenes; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D017338:Cladribine; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D053148:Caspase 3; D014740:Vidarabine; C024352:fludarabine; D000077185:Resveratrol