A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

Sung Kyun Ko, Jiyeon Kim, Deuk Chae Na, Sookil Park, Seong Hyun Park, Ji Young Hyun, Kyung Hwa Baek, Nam Doo Kim, Nak Kyoon Kim, Young Nyun Park, Kiwon Song, Injae Shin

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.

Original languageEnglish
Article number3008
Pages (from-to)391-403
Number of pages13
JournalChemistry and Biology
Volume22
Issue number3
DOIs
Publication statusPublished - 2015 Mar 19

Fingerprint

Adenosine Triphosphatases
Apoptosis
Affinity chromatography
Molecules
HSP70 Heat-Shock Proteins
Cell death
Caspases
Heat-Shock Proteins
Heterografts
Tumors
Animals
Cells
Neoplasms
HSP40 Heat-Shock Proteins
Affinity Chromatography
Cell Death
apoptozole
Phenotype
Therapeutics
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Ko, Sung Kyun ; Kim, Jiyeon ; Na, Deuk Chae ; Park, Sookil ; Park, Seong Hyun ; Hyun, Ji Young ; Baek, Kyung Hwa ; Kim, Nam Doo ; Kim, Nak Kyoon ; Park, Young Nyun ; Song, Kiwon ; Shin, Injae. / A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities. In: Chemistry and Biology. 2015 ; Vol. 22, No. 3. pp. 391-403.
@article{e45125e13c88491e9dc11e6b816966e0,
title = "A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities",
abstract = "Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.",
author = "Ko, {Sung Kyun} and Jiyeon Kim and Na, {Deuk Chae} and Sookil Park and Park, {Seong Hyun} and Hyun, {Ji Young} and Baek, {Kyung Hwa} and Kim, {Nam Doo} and Kim, {Nak Kyoon} and Park, {Young Nyun} and Kiwon Song and Injae Shin",
year = "2015",
month = "3",
day = "19",
doi = "10.1016/j.chembiol.2015.02.004",
language = "English",
volume = "22",
pages = "391--403",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "3",

}

Ko, SK, Kim, J, Na, DC, Park, S, Park, SH, Hyun, JY, Baek, KH, Kim, ND, Kim, NK, Park, YN, Song, K & Shin, I 2015, 'A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities', Chemistry and Biology, vol. 22, no. 3, 3008, pp. 391-403. https://doi.org/10.1016/j.chembiol.2015.02.004

A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities. / Ko, Sung Kyun; Kim, Jiyeon; Na, Deuk Chae; Park, Sookil; Park, Seong Hyun; Hyun, Ji Young; Baek, Kyung Hwa; Kim, Nam Doo; Kim, Nak Kyoon; Park, Young Nyun; Song, Kiwon; Shin, Injae.

In: Chemistry and Biology, Vol. 22, No. 3, 3008, 19.03.2015, p. 391-403.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A small molecule inhibitor of ATPase activity of HSP70 induces apoptosis and has antitumor activities

AU - Ko, Sung Kyun

AU - Kim, Jiyeon

AU - Na, Deuk Chae

AU - Park, Sookil

AU - Park, Seong Hyun

AU - Hyun, Ji Young

AU - Baek, Kyung Hwa

AU - Kim, Nam Doo

AU - Kim, Nak Kyoon

AU - Park, Young Nyun

AU - Song, Kiwon

AU - Shin, Injae

PY - 2015/3/19

Y1 - 2015/3/19

N2 - Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.

AB - Summary The heat shock protein HSP70 plays antiapoptotic and oncogenic roles, and thus its inhibition has been recognized as a potential avenue for anticancer therapy. Here we describe the small molecule, apoptozole (Az), which inhibits the ATPase activity of HSP70 by binding to its ATPase domain and, as a result, induces an array of apoptotic phenotypes in cancer cells. Affinity chromatography provides evidence that Az binds HSP70 but not other types of heat shock proteins including HSP40, HSP60, and HSP90. We also demonstrate that Az induces cancer cell death via caspase-dependent apoptosis by disrupting the interaction of HSP70 with APAF-1. Animal studies indicate that Az treatment retards tumor growth in a xenograft mouse model without affecting mouse viability. These studies suggest that Az will aid the development of new cancer therapies and serve as a chemical probe to gain a better understanding of the diverse functions of HSP70.

UR - http://www.scopus.com/inward/record.url?scp=84925463299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925463299&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2015.02.004

DO - 10.1016/j.chembiol.2015.02.004

M3 - Article

VL - 22

SP - 391

EP - 403

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9448

IS - 3

M1 - 3008

ER -