HSp90 inhibitors, geldanamycin and radicicol, enhance fisetin-induced cytotoxicity via induction of apoptosis in human colonic cancer cells

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Abstract

We revealed the cytotoxic effect of the flavonoid, fisetin (FIS), on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA) and radicicol (RAD). Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study.

Original languageEnglish
Article number987612
JournalEvidence-based Complementary and Alternative Medicine
Volume2013
DOIs
Publication statusPublished - 2013

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Colonic Neoplasms
Apoptosis
Caspase 3
Caspase 9
monorden
geldanamycin
fisetin
Proteins
bcl-X Protein
bcl-2-Associated X Protein
Caspase Inhibitors
Protein Stability
DNA
Ubiquitin
Matrix Metalloproteinases
Flavonoids
Western Blotting

ASJC Scopus subject areas

  • Complementary and alternative medicine

Cite this

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title = "HSp90 inhibitors, geldanamycin and radicicol, enhance fisetin-induced cytotoxicity via induction of apoptosis in human colonic cancer cells",
abstract = "We revealed the cytotoxic effect of the flavonoid, fisetin (FIS), on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA) and radicicol (RAD). Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study.",
author = "Wu, {Ming Shun} and Lien, {Gi Shih} and Shen, {Shing Chuan} and Yang, {Liang Yo} and Chen, {Yen Chou}",
year = "2013",
doi = "10.1155/2013/987612",
language = "English",
volume = "2013",
journal = "Evidence-based Complementary and Alternative Medicine",
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TY - JOUR

T1 - HSp90 inhibitors, geldanamycin and radicicol, enhance fisetin-induced cytotoxicity via induction of apoptosis in human colonic cancer cells

AU - Wu, Ming Shun

AU - Lien, Gi Shih

AU - Shen, Shing Chuan

AU - Yang, Liang Yo

AU - Chen, Yen Chou

PY - 2013

Y1 - 2013

N2 - We revealed the cytotoxic effect of the flavonoid, fisetin (FIS), on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA) and radicicol (RAD). Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study.

AB - We revealed the cytotoxic effect of the flavonoid, fisetin (FIS), on human COLO205 colon cancer cells in the presence and absence of the HSP90 inhibitors, geldanamycin (GA) and radicicol (RAD). Compared to FIS treatment alone of COLO205 cells, GA and RAD significantly enhanced FIS-induced cytotoxicity, increased expression of cleaved caspase-3 and the PAPR protein, and produced a greater density of DNA ladder formation. GA and RAD also reduced the MMPs with induction of caspase-9 protein cleavage in FIS-treated COLO205 cells. Increased caspase-3 and -9 activities were detected in COLO205 cells treated with FIS+GA or FIS+RAD, and the intensity of DNA ladder formation induced by FIS+GA was reduced by adding the caspase-3 inhibitor, DEVD-FMK. A decrease in Bcl-2 but not Bcl-XL or Bax protein by FIS+GA or FIS+RAD was identified in COLO205 cells by Western blotting. A reduction in p53 protein with increased ubiquitin-tagged proteins was observed in COLO205 cells treated with FIS+GA or FIS+RAD. Furthermore, GA and RAD reduced the stability of the p53 protein in COLO205 cells under FIS stimulation. The evidence supports HSP90 inhibitors possibly sensitizing human colon cancer cells to FIS-induced apoptosis, and treating colon cancer by combining HSP90 inhibitors with FIS deserves further in vivo study.

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