Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells

Banke Agarwal, Sanjay Bhendwal, Balazs Halmos, Steven F. Moss, William G. Ramey, Peter R. Holt

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

β-Hydroxy-β-methylglutaryl coA reductase inhibitors (HRIs) inhibit isoprenylation of several members of the Ras superfamily of proteins and therefore have important cellular effects, including the reduction of proliferation and increasing apoptosis. Significant toxicity at high doses has precluded the use of HRIs as a monotherapy for cancers. We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW 480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with differing sensitivity. Pretreatment with lovastatin significantly increased apoptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines. Lovastatin treatment resulted in decreased expression of the antiapoptotic protein bcl-2 and increased the expression of the proapoptotic protein bax. The addition of geranylgeranylpyrophospate (10 μM) prevented lovastatin-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 μM) was partially effective, whereas cotreatment with farnesyl pyrophosphate (100 μM) had no effect. These data imply that lovastatin acts by inhibiting geranylgeranylation and not farnesylation of target protein(s). Our data suggest that lovastatin may potentially be combined with 5-FU or cisplatin as chemotherapy for colon cancers.

Original languageEnglish (US)
Pages (from-to)2223-2229
Number of pages7
JournalClinical Cancer Research
Volume5
Issue number8
StatePublished - Aug 1999
Externally publishedYes

Fingerprint

Lovastatin
Colonic Neoplasms
Apoptosis
Fluorouracil
Cisplatin
Prenylation
Oxidoreductases
Protein Prenylation
ras Proteins
bcl-2-Associated X Protein
Cell Line
Mevalonic Acid
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Agarwal, B., Bhendwal, S., Halmos, B., Moss, S. F., Ramey, W. G., & Holt, P. R. (1999). Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clinical Cancer Research, 5(8), 2223-2229.

Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. / Agarwal, Banke; Bhendwal, Sanjay; Halmos, Balazs; Moss, Steven F.; Ramey, William G.; Holt, Peter R.

In: Clinical Cancer Research, Vol. 5, No. 8, 08.1999, p. 2223-2229.

Research output: Contribution to journalArticle

Agarwal, B, Bhendwal, S, Halmos, B, Moss, SF, Ramey, WG & Holt, PR 1999, 'Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells', Clinical Cancer Research, vol. 5, no. 8, pp. 2223-2229.
Agarwal, Banke ; Bhendwal, Sanjay ; Halmos, Balazs ; Moss, Steven F. ; Ramey, William G. ; Holt, Peter R. / Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 8. pp. 2223-2229.
@article{6ac7c3751fdc4f9ea540bf8eb14454e0,
title = "Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells",
abstract = "β-Hydroxy-β-methylglutaryl coA reductase inhibitors (HRIs) inhibit isoprenylation of several members of the Ras superfamily of proteins and therefore have important cellular effects, including the reduction of proliferation and increasing apoptosis. Significant toxicity at high doses has precluded the use of HRIs as a monotherapy for cancers. We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW 480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with differing sensitivity. Pretreatment with lovastatin significantly increased apoptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines. Lovastatin treatment resulted in decreased expression of the antiapoptotic protein bcl-2 and increased the expression of the proapoptotic protein bax. The addition of geranylgeranylpyrophospate (10 μM) prevented lovastatin-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 μM) was partially effective, whereas cotreatment with farnesyl pyrophosphate (100 μM) had no effect. These data imply that lovastatin acts by inhibiting geranylgeranylation and not farnesylation of target protein(s). Our data suggest that lovastatin may potentially be combined with 5-FU or cisplatin as chemotherapy for colon cancers.",
author = "Banke Agarwal and Sanjay Bhendwal and Balazs Halmos and Moss, {Steven F.} and Ramey, {William G.} and Holt, {Peter R.}",
year = "1999",
month = "8",
language = "English (US)",
volume = "5",
pages = "2223--2229",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells

AU - Agarwal, Banke

AU - Bhendwal, Sanjay

AU - Halmos, Balazs

AU - Moss, Steven F.

AU - Ramey, William G.

AU - Holt, Peter R.

PY - 1999/8

Y1 - 1999/8

N2 - β-Hydroxy-β-methylglutaryl coA reductase inhibitors (HRIs) inhibit isoprenylation of several members of the Ras superfamily of proteins and therefore have important cellular effects, including the reduction of proliferation and increasing apoptosis. Significant toxicity at high doses has precluded the use of HRIs as a monotherapy for cancers. We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW 480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with differing sensitivity. Pretreatment with lovastatin significantly increased apoptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines. Lovastatin treatment resulted in decreased expression of the antiapoptotic protein bcl-2 and increased the expression of the proapoptotic protein bax. The addition of geranylgeranylpyrophospate (10 μM) prevented lovastatin-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 μM) was partially effective, whereas cotreatment with farnesyl pyrophosphate (100 μM) had no effect. These data imply that lovastatin acts by inhibiting geranylgeranylation and not farnesylation of target protein(s). Our data suggest that lovastatin may potentially be combined with 5-FU or cisplatin as chemotherapy for colon cancers.

AB - β-Hydroxy-β-methylglutaryl coA reductase inhibitors (HRIs) inhibit isoprenylation of several members of the Ras superfamily of proteins and therefore have important cellular effects, including the reduction of proliferation and increasing apoptosis. Significant toxicity at high doses has precluded the use of HRIs as a monotherapy for cancers. We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells. In the colon cancer cell lines SW 480, HCT116, LoVo, and HT29, lovastatin induced apoptosis with differing sensitivity. Pretreatment with lovastatin significantly increased apoptosis induced by 5-fluorouracil (5-FU) or cisplatin in all four cell lines. Lovastatin treatment resulted in decreased expression of the antiapoptotic protein bcl-2 and increased the expression of the proapoptotic protein bax. The addition of geranylgeranylpyrophospate (10 μM) prevented lovastatin-induced augmentation of 5-FU and cisplatin-induced apoptosis; mevalonate (100 μM) was partially effective, whereas cotreatment with farnesyl pyrophosphate (100 μM) had no effect. These data imply that lovastatin acts by inhibiting geranylgeranylation and not farnesylation of target protein(s). Our data suggest that lovastatin may potentially be combined with 5-FU or cisplatin as chemotherapy for colon cancers.

UR - http://www.scopus.com/inward/record.url?scp=0032766426&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032766426&partnerID=8YFLogxK

M3 - Article

C2 - 10473109

AN - SCOPUS:0032766426

VL - 5

SP - 2223

EP - 2229

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 8

ER -