Exisulind (Sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis

Erik T. Goluboff, Ahmad Shabsigh, James A. Saidi, I. Bernard Weinstein, Nandita Mitra, Daniel Heitjan, Gary A. Piazza, Rifat Pamukcu, Ralph Buttyan, Carl A. Olsson

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Abstract

Objectives. Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. Methods. Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 107 LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. Results. Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P < 0.0001) but no change in the number of BrdU positive cells. Conclusions. This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

Original languageEnglish (US)
Pages (from-to)440-445
Number of pages6
JournalUrology
Volume53
Issue number2
DOIs
StatePublished - Feb 1 1999

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Heterografts
Nude Mice
Prostatic Neoplasms
Apoptosis
Growth
Diet
Maximum Tolerated Dose
Bromodeoxyuridine
Neoplasms
Anti-Inflammatory Agents
Pharmaceutical Preparations
Sulindac
Sulfones
In Situ Nick-End Labeling
Prostaglandin-Endoperoxide Synthases
Immunoassay
sulindac sulfone
Prostate
Control Groups

ASJC Scopus subject areas

  • Urology

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Exisulind (Sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis. / Goluboff, Erik T.; Shabsigh, Ahmad; Saidi, James A.; Weinstein, I. Bernard; Mitra, Nandita; Heitjan, Daniel; Piazza, Gary A.; Pamukcu, Rifat; Buttyan, Ralph; Olsson, Carl A.

In: Urology, Vol. 53, No. 2, 01.02.1999, p. 440-445.

Research output: Contribution to journalArticle

Goluboff, ET, Shabsigh, A, Saidi, JA, Weinstein, IB, Mitra, N, Heitjan, D, Piazza, GA, Pamukcu, R, Buttyan, R & Olsson, CA 1999, 'Exisulind (Sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis', Urology, vol. 53, no. 2, pp. 440-445. https://doi.org/10.1016/S0090-4295(98)00513-5
Goluboff, Erik T. ; Shabsigh, Ahmad ; Saidi, James A. ; Weinstein, I. Bernard ; Mitra, Nandita ; Heitjan, Daniel ; Piazza, Gary A. ; Pamukcu, Rifat ; Buttyan, Ralph ; Olsson, Carl A. / Exisulind (Sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis. In: Urology. 1999 ; Vol. 53, No. 2. pp. 440-445.
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title = "Exisulind (Sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis",
abstract = "Objectives. Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. Methods. Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 107 LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05{\%} Exisulind (40{\%} of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1{\%} Exisulind (80{\%} MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. Results. Tumors grew by 158{\%}, 24{\%}, and 18{\%} for the control and 0.05{\%} and 0.1{\%} Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P < 0.0001) but no change in the number of BrdU positive cells. Conclusions. This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.",
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T1 - Exisulind (Sulindac sulfone) suppresses growth of human prostate cancer in a nude mouse xenograft model by increasing apoptosis

AU - Goluboff, Erik T.

AU - Shabsigh, Ahmad

AU - Saidi, James A.

AU - Weinstein, I. Bernard

AU - Mitra, Nandita

AU - Heitjan, Daniel

AU - Piazza, Gary A.

AU - Pamukcu, Rifat

AU - Buttyan, Ralph

AU - Olsson, Carl A.

PY - 1999/2/1

Y1 - 1999/2/1

N2 - Objectives. Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. Methods. Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 107 LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. Results. Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P < 0.0001) but no change in the number of BrdU positive cells. Conclusions. This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

AB - Objectives. Recent studies have shown that Exisulind, a sulfone metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac, has inhibitory activity in vitro with cultured human prostate cancer cells. To determine whether this effect might be pharmacologically relevant in vivo, we tested whether Exisulind therapy could suppress the growth of human prostate cancer cells in a nude mouse xenograft model. Methods. Thirty athymic nude mice were injected subcutaneously in the flank with 1 x 107 LNCaP human prostate tumor cells. All mice received a control diet for 21 days. One group of mice was continued on this control diet for an additional 4 weeks, a second group was switched to a diet supplemented with 0.05% Exisulind (40% of maximal tolerated dose [MTD]), and a third group was switched to a diet supplemented with 0.1% Exisulind (80% MTD) for the additional 4 weeks. Tumor growth was measured through the 4-week test period, and subsequently tissue sections from the various groups were tested for apoptotic and dividing cells by quantified use of the TUNEL assay and a bromodeoxyuridine (BrdU) incorporation immunoassay. Results. Tumors grew by 158%, 24%, and 18% for the control and 0.05% and 0.1% Exisulind groups, respectively (P = 0.02) during the 4-week test period. Immunohistochemical studies on excised tumors showed an increased number of apoptotic bodies in the treated groups versus the control group (P < 0.0001) but no change in the number of BrdU positive cells. Conclusions. This is the first study to show a direct in vivo effect of an NSAID-derived drug, lacking cyclooxygenase inhibitory activity, in a xenograft model of prostate cancer. Clinical studies to evaluate the effects of Exisulind against prostate cancer in humans are warranted.

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