Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis

G. A. Piazza, A. L K Rahm, M. Krutzsch, G. Sperl, N. S. Paranka, P. H. Gross, K. Brendel, R. W. Burt, David S Alberts, R. Pamukcu, D. J. Ahnen

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)3110-3116
Number of pages7
JournalCancer Research
Volume55
Issue number14
StatePublished - 1995
Externally publishedYes

Fingerprint

Antineoplastic Agents
Apoptosis
Sulindac
Growth
HT29 Cells
Prostaglandins
Pharmaceutical Preparations
Sulfides
Carcinogenesis
Cultured Tumor Cells
Sulfones
Adenomatous Polyposis Coli
sulindac sulfone
sulindac sulfide
Prodrugs
Cell Cycle Checkpoints
Tumor Cell Line
Baths
Adenoma
Rodentia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Piazza, G. A., Rahm, A. L. K., Krutzsch, M., Sperl, G., Paranka, N. S., Gross, P. H., ... Ahnen, D. J. (1995). Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Research, 55(14), 3110-3116.

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 journalArticle

Piazza, GA, Rahm, ALK, Krutzsch, M, Sperl, G, Paranka, NS, Gross, PH, Brendel, K, Burt, RW, Alberts, DS, Pamukcu, R & Ahnen, DJ 1995, 'Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis', Cancer Research, vol. 55, no. 14, pp. 3110-3116.
Piazza GA, Rahm ALK, Krutzsch M, Sperl G, Paranka NS, Gross PH et al. Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. Cancer Research. 1995;55(14):3110-3116.
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. / Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. In: Cancer Research. 1995 ; Vol. 55, No. 14. pp. 3110-3116.
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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.",
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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.

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