N-Benzyladriamycin-14-valerate (AD 198) cytotoxicty circumvents Bcr-Abl anti-apoptotic signaling in human leukemia cells and also potentiates imatinib cytotoxicity

Leonard Lothstein, Luydmila Savranskaya, Trevor W. Sweatman

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Bcr-Abl activity in chronic myelogenous leukemia (CML) results in dysregulated cell proliferation and resistance against multiple cytotoxic agents due to the constitutive activation of proliferative signaling pathways. Currently, the most effective treatment of CML is the inhibition of Bcr-Abl activity by imatinib mesylate (Gleevec®). Imatinib efficacy is limited by development of resistance through either expression of Bcr-Abl variants that bind imatinib less avidly, increased expression of Bcr-Abl, or expression of multidrug transport proteins. N-Benzyladriamycin-14-valerate (AD 198) is a novel antitumor PKC activating agent that triggers rapid apoptosis through PKC-δ activation and mitochondrial depolarization in a manner that is unaffected by Bcl-2 expression. We demonstrate that Bcr-Abl expression does not confer resistance to AD 198. Further, AD 198 rapidly induces Erk1/2 and STAT5 phosphorylation prior to cytochrome c release from mitochondria, indicating that proliferative pathways are active even as drug-treated cells undergo apoptosis. At sub-cytotoxic doses, AD 198 and its cellular metabolite, N-benzyladriamycin (AD 288) sensitize CML cells to imatinib through a supra-additive reduction in the level of Bcr-Abl protein expression. These results suggest that AD 198 is an effective treatment for CML both in combination with imatinib and alone against imatinib-resistant CML cells.

Original languageEnglish (US)
Pages (from-to)1085-1095
Number of pages11
JournalLeukemia Research
Volume31
Issue number8
DOIs
StatePublished - Jan 1 2007

Fingerprint

Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Apoptosis
Cytotoxins
Cytochromes c
Imatinib Mesylate
N-benzyladriamycin-14-valerate
Carrier Proteins
Mitochondria
Phosphorylation
Cell Proliferation
Pharmaceutical Preparations
Proteins
N-benzyladriamycin

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

N-Benzyladriamycin-14-valerate (AD 198) cytotoxicty circumvents Bcr-Abl anti-apoptotic signaling in human leukemia cells and also potentiates imatinib cytotoxicity. / Lothstein, Leonard; Savranskaya, Luydmila; Sweatman, Trevor W.

In: Leukemia Research, Vol. 31, No. 8, 01.01.2007, p. 1085-1095.

Research output: Contribution to journalArticle

@article{3f6c13b0aebe4724a27eb380a247e605,
title = "N-Benzyladriamycin-14-valerate (AD 198) cytotoxicty circumvents Bcr-Abl anti-apoptotic signaling in human leukemia cells and also potentiates imatinib cytotoxicity",
abstract = "Bcr-Abl activity in chronic myelogenous leukemia (CML) results in dysregulated cell proliferation and resistance against multiple cytotoxic agents due to the constitutive activation of proliferative signaling pathways. Currently, the most effective treatment of CML is the inhibition of Bcr-Abl activity by imatinib mesylate (Gleevec{\circledR}). Imatinib efficacy is limited by development of resistance through either expression of Bcr-Abl variants that bind imatinib less avidly, increased expression of Bcr-Abl, or expression of multidrug transport proteins. N-Benzyladriamycin-14-valerate (AD 198) is a novel antitumor PKC activating agent that triggers rapid apoptosis through PKC-δ activation and mitochondrial depolarization in a manner that is unaffected by Bcl-2 expression. We demonstrate that Bcr-Abl expression does not confer resistance to AD 198. Further, AD 198 rapidly induces Erk1/2 and STAT5 phosphorylation prior to cytochrome c release from mitochondria, indicating that proliferative pathways are active even as drug-treated cells undergo apoptosis. At sub-cytotoxic doses, AD 198 and its cellular metabolite, N-benzyladriamycin (AD 288) sensitize CML cells to imatinib through a supra-additive reduction in the level of Bcr-Abl protein expression. These results suggest that AD 198 is an effective treatment for CML both in combination with imatinib and alone against imatinib-resistant CML cells.",
author = "Leonard Lothstein and Luydmila Savranskaya and Sweatman, {Trevor W.}",
year = "2007",
month = "1",
day = "1",
doi = "10.1016/j.leukres.2006.11.003",
language = "English (US)",
volume = "31",
pages = "1085--1095",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",
number = "8",

}

TY - JOUR

T1 - N-Benzyladriamycin-14-valerate (AD 198) cytotoxicty circumvents Bcr-Abl anti-apoptotic signaling in human leukemia cells and also potentiates imatinib cytotoxicity

AU - Lothstein, Leonard

AU - Savranskaya, Luydmila

AU - Sweatman, Trevor W.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Bcr-Abl activity in chronic myelogenous leukemia (CML) results in dysregulated cell proliferation and resistance against multiple cytotoxic agents due to the constitutive activation of proliferative signaling pathways. Currently, the most effective treatment of CML is the inhibition of Bcr-Abl activity by imatinib mesylate (Gleevec®). Imatinib efficacy is limited by development of resistance through either expression of Bcr-Abl variants that bind imatinib less avidly, increased expression of Bcr-Abl, or expression of multidrug transport proteins. N-Benzyladriamycin-14-valerate (AD 198) is a novel antitumor PKC activating agent that triggers rapid apoptosis through PKC-δ activation and mitochondrial depolarization in a manner that is unaffected by Bcl-2 expression. We demonstrate that Bcr-Abl expression does not confer resistance to AD 198. Further, AD 198 rapidly induces Erk1/2 and STAT5 phosphorylation prior to cytochrome c release from mitochondria, indicating that proliferative pathways are active even as drug-treated cells undergo apoptosis. At sub-cytotoxic doses, AD 198 and its cellular metabolite, N-benzyladriamycin (AD 288) sensitize CML cells to imatinib through a supra-additive reduction in the level of Bcr-Abl protein expression. These results suggest that AD 198 is an effective treatment for CML both in combination with imatinib and alone against imatinib-resistant CML cells.

AB - Bcr-Abl activity in chronic myelogenous leukemia (CML) results in dysregulated cell proliferation and resistance against multiple cytotoxic agents due to the constitutive activation of proliferative signaling pathways. Currently, the most effective treatment of CML is the inhibition of Bcr-Abl activity by imatinib mesylate (Gleevec®). Imatinib efficacy is limited by development of resistance through either expression of Bcr-Abl variants that bind imatinib less avidly, increased expression of Bcr-Abl, or expression of multidrug transport proteins. N-Benzyladriamycin-14-valerate (AD 198) is a novel antitumor PKC activating agent that triggers rapid apoptosis through PKC-δ activation and mitochondrial depolarization in a manner that is unaffected by Bcl-2 expression. We demonstrate that Bcr-Abl expression does not confer resistance to AD 198. Further, AD 198 rapidly induces Erk1/2 and STAT5 phosphorylation prior to cytochrome c release from mitochondria, indicating that proliferative pathways are active even as drug-treated cells undergo apoptosis. At sub-cytotoxic doses, AD 198 and its cellular metabolite, N-benzyladriamycin (AD 288) sensitize CML cells to imatinib through a supra-additive reduction in the level of Bcr-Abl protein expression. These results suggest that AD 198 is an effective treatment for CML both in combination with imatinib and alone against imatinib-resistant CML cells.

UR - http://www.scopus.com/inward/record.url?scp=34249898932&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249898932&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2006.11.003

DO - 10.1016/j.leukres.2006.11.003

M3 - Article

VL - 31

SP - 1085

EP - 1095

JO - Leukemia Research

JF - Leukemia Research

SN - 0145-2126

IS - 8

ER -