Antiproliferative and proapoptotic activity of GUT-70 mediated through potent inhibition of Hsp90 in mantle cell lymphoma.

Abstract

BACKGROUND:

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, requiring novel anticancer strategies.

METHODS:

Mantle cell lymphoma cell lines with known p53 status were treated with GUT-70, a tricyclic coumarin derived from Calophyllum brasiliense, and the biological and biochemical consequences of GUT-70 were studied.

RESULTS:

GUT-70 markedly reduced cell proliferation/viability through G(1) cell cycle arrest and increased apoptosis, with greater sensitivity in mutant (mt)-p53-expressing MCL cells than in wild-type (wt)-p53-bearing cells. Mechanistically, GUT-70 showed binding affinity to heat-shock protein 90 (Hsp90) and ubiquitin-dependent proteasomal degradation of Hsp90 client proteins, including cyclin D1, Raf-1, Akt, and mt-p53. Depletion of constitutively overexpressed cyclin D1 by GUT-70 was accompanied by p27 accumulation and decreased Rb phosphorylation. GUT-70 induced mitochondrial apoptosis with Noxa upregulation and Mcl-1 downregulation in mt-p53 cells, but Mcl-1 accumulation in wt-p53 cells. Noxa and Mcl-1 were coimmunoprecipitated, and activated BAK. Treatment with a combination of GUT-70 and bortezomib or doxorubicin had synergistic antiproliferative effects in MCL cells that were independent of p53 status.

CONCLUSION:

GUT-70 has pronounced antiproliferative effects in MCL with mt-p53, a known negative prognostic factor for MCL, through Hsp90 inhibition. These findings suggest that GUT-70 has potential utility for the treatment of MCL.

• Authors: L Jin, Y Tabe, S Kimura, Y Zhou, J Kuroda, H Asou, T Inaba, M Konopleva, M Andreeff, T Miida
• Journal: British journal of cancer (Br J Cancer) Vol. 104 Issue 1 Pg. 91-100 (Jan 04 2011) ISSN: 1532-1827 [Electronic] England
• PMID: 21139584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• Coumarins
• GUT-70
• HSP90 Heat-Shock Proteins
• PMAIP1 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Pyrazines
• RNA, Messenger
• Tumor Suppressor Protein p53
• bcl-2 Homologous Antagonist-Killer Protein
• Cyclin D1
• Bortezomib
• Oncogene Protein v-akt
• Proto-Oncogene Proteins c-raf

Topics

• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Boronic Acids (therapeutic use)
• Bortezomib
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Coumarins (pharmacology)
• Cyclin D1 (genetics, metabolism)
• Drug Synergism
• Drug Therapy, Combination
• Flow Cytometry
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Lymphoma, Mantle-Cell (drug therapy, metabolism, pathology)
• Mutation (genetics)
• Oncogene Protein v-akt (genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Proto-Oncogene Proteins c-raf (genetics, metabolism)
• Pyrazines (therapeutic use)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)
• bcl-2 Homologous Antagonist-Killer Protein (genetics, metabolism)