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Cell cycle and apoptosis regulatory protein (CARP)-1 is a novel, adriamycin-inducible, diffuse large B-cell lymphoma (DLBL) growth suppressor.

AbstractUNLABELLED:
Diffuse large B-cell lymphoma (DLCL) accounts for 30-40% of adult non-Hodgkin's Lymphoma (NHL). Current anti-NHL therapies often target cellular growth suppression pathways and include R-CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone plus monoclonal anti-CD20 antibody rituximab). However, since many patients relapse, resistant cells to these therapies remain a significant problem and necessitate development of new intervention strategies. Cell cycle and apoptosis regulatory protein (CARP)-1 functions in a biphasic manner to regulate growth factor as well as chemotherapy (adriamycin, etoposide, or iressa)-dependent signaling.
PURPOSE:
To determine whether CARP-1 is a novel suppressor of lymphoma growth.
METHODS:
Flow cytometric analyses coupled with Western immunoblotting, cell growth, apoptosis, and immunocytochemistry methodologies were utilized to determine CARP-1-dependent lymphoma growth inhibition in vitro and in vivo.
RESULTS:
CARP-1 expression correlated with activated caspase-3 and inversely correlated with activated Akt in DLCL. Exposure to adriamycin stimulated CARP-1 expression and inhibited growth of Raji cells, but not CHOP-resistant WSU-DLCL2 cells. Expression of wild-type CARP-1 or its apoptosis-inducing mutants inhibited growth of Raji as well as CHOP-resistant WSU-DLCL2 cells, in part by activating caspase-9 and apoptosis. Since CARP-1 harbors multiple, apoptosis-promoting subdomains, we investigated whether epigenetic compensation of CARP-1 function by intracellular delivery of trans-activator of transcription (TAT) domain-tagged CARP-1 peptide(s) will inhibit lymphoma growth. Treatments with TAT-tagged CARP-1 peptides suppressed growth of the Raji and WSU-DLCL2 cells by stimulating apoptosis. TAT-CARP-1 (1-198) as well as (896-1150) peptides also suppressed growth of WSU-DLCL2 cell-derived tumor xenografts in SCID mice, while administration of TAT-CARP-1 (1-198) also inhibited growth of WSU-FSCCL cell-derived ascites and prolonged host survival.
CONCLUSION:
CARP-1 is a suppressor of NHL growth and could be exploited for targeting the resistant DLCL.
AuthorsEdi Levi, Liyue Zhang, Amro Aboukameel, Sunny Rishi, Ramzi M Mohammad, Lisa Polin, James S Hatfield, Arun K Rishi
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 6 Pg. 1401-13 (Jun 2011) ISSN: 1432-0843 [Electronic] Germany
PMID20809119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Antibiotics, Antineoplastic
  • Apoptosis Regulatory Proteins
  • CCAR1 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Peptide Fragments
  • Doxorubicin
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
Topics
  • Animals
  • Antibiotics, Antineoplastic (pharmacology)
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Carrier Proteins (biosynthesis, genetics, physiology)
  • Caspase 3 (metabolism)
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Doxorubicin (pharmacology)
  • Humans
  • Lymphoma, Large B-Cell, Diffuse (metabolism, pathology)
  • Mice
  • Mice, SCID
  • Mutation
  • NIH 3T3 Cells
  • Neoplasm Transplantation
  • Peptide Fragments (pharmacology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Transplantation, Heterologous

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