Abstract
The nonsteroidal anti-inflammatory drug sulindac is known to inhibit chemical carcinogenesis in rodent models and cause regression of adenomas in patients with adenomatous polyposis coli. Sulindac is a prodrug that is metabolized tn a pharmacologically active sulfide derivative that potently inhibits prostaglandin synthesis. Recent studies, however, have shown that a sulfone derivative of sulindac, which essentially lacks prostaglandin synthesis inhibitory activity, also inhibits chemical carcinogenesis, suggesting that reduction of prostaglandin levels is not necessary for the antineoplastic activity of this class of drugs. Both sulindac sulfide and the sulfone inhibit the growth of cultured tumor cells, although the cellular mechanism(s) responsible for the antineoplastic activity of sulindac derivatives is unknown. In this study, we investigated the effects of sulindac sulfide and sulfone on the proliferation, differentiation, and apoptosis of HT-29 human colon carcinoma cells. Sulindac sulfide and sulfone significantly reduced cell number in bath preconfluent and confluent cultures of HT-29 cells with the sulfide showing approximately 4-fold greater potency. In addition tn HT-29 cells, both drugs inhibited the growth of a variety of tumor cell lines derived from other tissues, as well as normal epithelial cells and fibroblasts. Neither sulindac sulfide nor sulfone inhibited cell proliferation under conditions where the drugs were growth inhibitory. Only under specific conditions involving mitogenic stimulation did sulindac sulfide and sulfone cause cell cycle arrest. Neither sulindac sulfide nor the surf one induced differentiation of HT-29 cells, but both drugs strongly induced apoptosis. The apoptotic response to sulindac sulfide and sulfone was both time- and dose-dependent and involved a mechanism independent of their inhibitory effect on cell cycle progression. These data suggest that apoptosis is responsible for the cell growth inhibitory activity of sulindac sulfide and sulfone and represents a potential mechanism for the antineoplastic activity of these drugs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3110-3116 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 55 |
| Issue number | 14 |
| State | Published - 1995 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. / Piazza, G. A.; Rahm, A. L K; Krutzsch, M.; Sperl, G.; Paranka, N. S.; Gross, P. H.; Brendel, K.; Burt, R. W.; Alberts, David S; Pamukcu, R.; Ahnen, D. J.
In: Cancer Research, Vol. 55, No. 14, 1995, p. 3110-3116.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis
AU - Piazza, G. A.
AU - Rahm, A. L K
AU - Krutzsch, M.
AU - Sperl, G.
AU - Paranka, N. S.
AU - Gross, P. H.
AU - Brendel, K.
AU - Burt, R. W.
AU - Alberts, David S
AU - Pamukcu, R.
AU - Ahnen, D. J.
PY - 1995
Y1 - 1995
N2 - The nonsteroidal anti-inflammatory drug sulindac is known to inhibit chemical carcinogenesis in rodent models and cause regression of adenomas in patients with adenomatous polyposis coli. Sulindac is a prodrug that is metabolized tn a pharmacologically active sulfide derivative that potently inhibits prostaglandin synthesis. Recent studies, however, have shown that a sulfone derivative of sulindac, which essentially lacks prostaglandin synthesis inhibitory activity, also inhibits chemical carcinogenesis, suggesting that reduction of prostaglandin levels is not necessary for the antineoplastic activity of this class of drugs. Both sulindac sulfide and the sulfone inhibit the growth of cultured tumor cells, although the cellular mechanism(s) responsible for the antineoplastic activity of sulindac derivatives is unknown. In this study, we investigated the effects of sulindac sulfide and sulfone on the proliferation, differentiation, and apoptosis of HT-29 human colon carcinoma cells. Sulindac sulfide and sulfone significantly reduced cell number in bath preconfluent and confluent cultures of HT-29 cells with the sulfide showing approximately 4-fold greater potency. In addition tn HT-29 cells, both drugs inhibited the growth of a variety of tumor cell lines derived from other tissues, as well as normal epithelial cells and fibroblasts. Neither sulindac sulfide nor sulfone inhibited cell proliferation under conditions where the drugs were growth inhibitory. Only under specific conditions involving mitogenic stimulation did sulindac sulfide and sulfone cause cell cycle arrest. Neither sulindac sulfide nor the surf one induced differentiation of HT-29 cells, but both drugs strongly induced apoptosis. The apoptotic response to sulindac sulfide and sulfone was both time- and dose-dependent and involved a mechanism independent of their inhibitory effect on cell cycle progression. These data suggest that apoptosis is responsible for the cell growth inhibitory activity of sulindac sulfide and sulfone and represents a potential mechanism for the antineoplastic activity of these drugs.
AB - The nonsteroidal anti-inflammatory drug sulindac is known to inhibit chemical carcinogenesis in rodent models and cause regression of adenomas in patients with adenomatous polyposis coli. Sulindac is a prodrug that is metabolized tn a pharmacologically active sulfide derivative that potently inhibits prostaglandin synthesis. Recent studies, however, have shown that a sulfone derivative of sulindac, which essentially lacks prostaglandin synthesis inhibitory activity, also inhibits chemical carcinogenesis, suggesting that reduction of prostaglandin levels is not necessary for the antineoplastic activity of this class of drugs. Both sulindac sulfide and the sulfone inhibit the growth of cultured tumor cells, although the cellular mechanism(s) responsible for the antineoplastic activity of sulindac derivatives is unknown. In this study, we investigated the effects of sulindac sulfide and sulfone on the proliferation, differentiation, and apoptosis of HT-29 human colon carcinoma cells. Sulindac sulfide and sulfone significantly reduced cell number in bath preconfluent and confluent cultures of HT-29 cells with the sulfide showing approximately 4-fold greater potency. In addition tn HT-29 cells, both drugs inhibited the growth of a variety of tumor cell lines derived from other tissues, as well as normal epithelial cells and fibroblasts. Neither sulindac sulfide nor sulfone inhibited cell proliferation under conditions where the drugs were growth inhibitory. Only under specific conditions involving mitogenic stimulation did sulindac sulfide and sulfone cause cell cycle arrest. Neither sulindac sulfide nor the surf one induced differentiation of HT-29 cells, but both drugs strongly induced apoptosis. The apoptotic response to sulindac sulfide and sulfone was both time- and dose-dependent and involved a mechanism independent of their inhibitory effect on cell cycle progression. These data suggest that apoptosis is responsible for the cell growth inhibitory activity of sulindac sulfide and sulfone and represents a potential mechanism for the antineoplastic activity of these drugs.
UR - http://www.scopus.com/inward/record.url?scp=0029035070&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029035070&partnerID=8YFLogxK
M3 - Article
C2 - 7606732
AN - SCOPUS:0029035070
VL - 55
SP - 3110
EP - 3116
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 14
ER -