Abstract
BACKGROUND: Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm, characterized by clonal expansion of CD5 positive B cells with constitutive activation of survival pathways including NF-kB. Pentoxifylline, a xanthine-derivative compound indicated for the treatment of microvascular disturbancies, has been suggested to have anti-proliferative and anti-metastatic activities in various types of cancer. In the present study we extend these data showing one of the potential molecular mechanisms through which Pentoxifylline may promote apoptosis in CLL clonal lymphocytes.
METHODS: Peripheral blood mononuclear cells were isolated from 15 CLL patients 0 RAI stage and 15 healthy volunteers and treated for 24 and 48 hours with Pentoxifylline. Apoptosis induction was evaluated through Annexin V and TUNEL assays. Mitochondrial membrane potential depolarization analysis, active Caspase-3 assay, reactive oxygen species generation and Western Blot were assessed to further investigate the alterations induced by Pentoxifylline.
RESULTS: We observed a statistically significant occurrence of apoptosis, DNA fragmentation and active Caspase-3 in lymphocytes from CLL patients compared to healthy volunteers after 48 hours of Pentoxifylline treatment. To clarify the molecular mechanism of the drug, we also evaluated the expression levels of NF-kB/p65 and its related proteins. In treated CLL cells, NF-kB/p65 was significantly decreased in comparison to normal cells, whereas we observed a less marked reduction of Bcl-2 expression. The treatment also induced a decrease of Mcl-1 in CLL cells with a greater down-regulation of the anti-apoptotic alternatively spliced isoform.
CONCLUSION: These findings showed that Pentoxifylline induced apoptosis in leukemic cells through a molecular mechanism that involves the NF-kB signaling.
| Original language | English |
|---|---|
| Pages (from-to) | 287-294 |
| Number of pages | 8 |
| Journal | Mini-Reviews in Medicinal Chemistry |
| Volume | 18 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2018 |
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Keywords
- Antineoplastic Agents
- Apoptosis
- Cells, Cultured
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukocytes, Mononuclear
- Membrane Potential, Mitochondrial
- NF-kappa B
- Pentoxifylline
- Proto-Oncogene Proteins c-bcl-2
- Structure-Activity Relationship
- Journal Article
Cite this
Pentoxifylline-Induced Apoptosis in Chronic Lymphocytic Leukemia : New Insights into Molecular Mechanism. / Napolitano, Roberta; De Matteis, Serena; Lucchesi, Alessandro; Carloni, Silvia; Cangini, Delia; Musuraca, Gerardo; Liardo, Eliana Valentina; Norata, Marianna; Fattori, Pier Paolo.
In: Mini-Reviews in Medicinal Chemistry, Vol. 18, No. 3, 2018, p. 287-294.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pentoxifylline-Induced Apoptosis in Chronic Lymphocytic Leukemia
T2 - New Insights into Molecular Mechanism
AU - Napolitano, Roberta
AU - De Matteis, Serena
AU - Lucchesi, Alessandro
AU - Carloni, Silvia
AU - Cangini, Delia
AU - Musuraca, Gerardo
AU - Liardo, Eliana Valentina
AU - Norata, Marianna
AU - Fattori, Pier Paolo
N1 - Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
PY - 2018
Y1 - 2018
N2 - BACKGROUND: Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm, characterized by clonal expansion of CD5 positive B cells with constitutive activation of survival pathways including NF-kB. Pentoxifylline, a xanthine-derivative compound indicated for the treatment of microvascular disturbancies, has been suggested to have anti-proliferative and anti-metastatic activities in various types of cancer. In the present study we extend these data showing one of the potential molecular mechanisms through which Pentoxifylline may promote apoptosis in CLL clonal lymphocytes.METHODS: Peripheral blood mononuclear cells were isolated from 15 CLL patients 0 RAI stage and 15 healthy volunteers and treated for 24 and 48 hours with Pentoxifylline. Apoptosis induction was evaluated through Annexin V and TUNEL assays. Mitochondrial membrane potential depolarization analysis, active Caspase-3 assay, reactive oxygen species generation and Western Blot were assessed to further investigate the alterations induced by Pentoxifylline.RESULTS: We observed a statistically significant occurrence of apoptosis, DNA fragmentation and active Caspase-3 in lymphocytes from CLL patients compared to healthy volunteers after 48 hours of Pentoxifylline treatment. To clarify the molecular mechanism of the drug, we also evaluated the expression levels of NF-kB/p65 and its related proteins. In treated CLL cells, NF-kB/p65 was significantly decreased in comparison to normal cells, whereas we observed a less marked reduction of Bcl-2 expression. The treatment also induced a decrease of Mcl-1 in CLL cells with a greater down-regulation of the anti-apoptotic alternatively spliced isoform.CONCLUSION: These findings showed that Pentoxifylline induced apoptosis in leukemic cells through a molecular mechanism that involves the NF-kB signaling.
AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm, characterized by clonal expansion of CD5 positive B cells with constitutive activation of survival pathways including NF-kB. Pentoxifylline, a xanthine-derivative compound indicated for the treatment of microvascular disturbancies, has been suggested to have anti-proliferative and anti-metastatic activities in various types of cancer. In the present study we extend these data showing one of the potential molecular mechanisms through which Pentoxifylline may promote apoptosis in CLL clonal lymphocytes.METHODS: Peripheral blood mononuclear cells were isolated from 15 CLL patients 0 RAI stage and 15 healthy volunteers and treated for 24 and 48 hours with Pentoxifylline. Apoptosis induction was evaluated through Annexin V and TUNEL assays. Mitochondrial membrane potential depolarization analysis, active Caspase-3 assay, reactive oxygen species generation and Western Blot were assessed to further investigate the alterations induced by Pentoxifylline.RESULTS: We observed a statistically significant occurrence of apoptosis, DNA fragmentation and active Caspase-3 in lymphocytes from CLL patients compared to healthy volunteers after 48 hours of Pentoxifylline treatment. To clarify the molecular mechanism of the drug, we also evaluated the expression levels of NF-kB/p65 and its related proteins. In treated CLL cells, NF-kB/p65 was significantly decreased in comparison to normal cells, whereas we observed a less marked reduction of Bcl-2 expression. The treatment also induced a decrease of Mcl-1 in CLL cells with a greater down-regulation of the anti-apoptotic alternatively spliced isoform.CONCLUSION: These findings showed that Pentoxifylline induced apoptosis in leukemic cells through a molecular mechanism that involves the NF-kB signaling.
KW - Antineoplastic Agents
KW - Apoptosis
KW - Cells, Cultured
KW - Dose-Response Relationship, Drug
KW - Drug Screening Assays, Antitumor
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Leukocytes, Mononuclear
KW - Membrane Potential, Mitochondrial
KW - NF-kappa B
KW - Pentoxifylline
KW - Proto-Oncogene Proteins c-bcl-2
KW - Structure-Activity Relationship
KW - Journal Article
U2 - 10.2174/1389557517666171002162258
DO - 10.2174/1389557517666171002162258
M3 - Article
C2 - 28969553
VL - 18
SP - 287
EP - 294
JO - Mini-Reviews in Medicinal Chemistry
JF - Mini-Reviews in Medicinal Chemistry
SN - 1389-5575
IS - 3
ER -