AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

H. Yao, E. Ashihara, J. W. Strovel, Y. Nakagawa, J. Kuroda, R. Nagao, R. Tanaka, A. Yokota, M. Takeuchi, Y. Hayashi, C. Shimazaki, M. Taniwaki, K. Strand, J. Padia, H. Hirai, S. Kimura, T. Maekawa

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

Original languageEnglish
Article numbere43
JournalBlood Cancer Journal
Volume1
Issue number11
DOIs
Publication statusPublished - Nov 1 2011
Externally publishedYes

Fingerprint

Catenins
Multiple Myeloma
Plasma Cell Neoplasms
TCF Transcription Factors
Wnt Signaling Pathway
Cyclin D1
Drug Discovery
RNA Interference
Libraries
Theoretical Models
Cell Proliferation
Technology

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

Cite this

AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. / Yao, H.; Ashihara, E.; Strovel, J. W.; Nakagawa, Y.; Kuroda, J.; Nagao, R.; Tanaka, R.; Yokota, A.; Takeuchi, M.; Hayashi, Y.; Shimazaki, C.; Taniwaki, M.; Strand, K.; Padia, J.; Hirai, H.; Kimura, S.; Maekawa, T.

In: Blood Cancer Journal, Vol. 1, No. 11, e43, 01.11.2011.

Research output: Contribution to journalArticle

Yao, H, Ashihara, E, Strovel, JW, Nakagawa, Y, Kuroda, J, Nagao, R, Tanaka, R, Yokota, A, Takeuchi, M, Hayashi, Y, Shimazaki, C, Taniwaki, M, Strand, K, Padia, J, Hirai, H, Kimura, S & Maekawa, T 2011, 'AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model', Blood Cancer Journal, vol. 1, no. 11, e43. https://doi.org/10.1038/bcj.2011.41
Yao, H. ; Ashihara, E. ; Strovel, J. W. ; Nakagawa, Y. ; Kuroda, J. ; Nagao, R. ; Tanaka, R. ; Yokota, A. ; Takeuchi, M. ; Hayashi, Y. ; Shimazaki, C. ; Taniwaki, M. ; Strand, K. ; Padia, J. ; Hirai, H. ; Kimura, S. ; Maekawa, T. / AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model. In: Blood Cancer Journal. 2011 ; Vol. 1, No. 11.
@article{d403cd1aac424be18d710ec7127828d7,
title = "AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model",
abstract = "Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.",
author = "H. Yao and E. Ashihara and Strovel, {J. W.} and Y. Nakagawa and J. Kuroda and R. Nagao and R. Tanaka and A. Yokota and M. Takeuchi and Y. Hayashi and C. Shimazaki and M. Taniwaki and K. Strand and J. Padia and H. Hirai and S. Kimura and T. Maekawa",
year = "2011",
month = "11",
day = "1",
doi = "10.1038/bcj.2011.41",
language = "English",
volume = "1",
journal = "Blood Cancer Journal",
issn = "2044-5385",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

AU - Yao, H.

AU - Ashihara, E.

AU - Strovel, J. W.

AU - Nakagawa, Y.

AU - Kuroda, J.

AU - Nagao, R.

AU - Tanaka, R.

AU - Yokota, A.

AU - Takeuchi, M.

AU - Hayashi, Y.

AU - Shimazaki, C.

AU - Taniwaki, M.

AU - Strand, K.

AU - Padia, J.

AU - Hirai, H.

AU - Kimura, S.

AU - Maekawa, T.

PY - 2011/11/1

Y1 - 2011/11/1

N2 - Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

AB - Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery.

UR - http://www.scopus.com/inward/record.url?scp=84863921921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863921921&partnerID=8YFLogxK

U2 - 10.1038/bcj.2011.41

DO - 10.1038/bcj.2011.41

M3 - Article

C2 - 22829079

AN - SCOPUS:84863921921

VL - 1

JO - Blood Cancer Journal

JF - Blood Cancer Journal

SN - 2044-5385

IS - 11

M1 - e43

ER -