Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways

Joseph C. Klink, Alok K. Tewari, Elizabeth M. Masko, Jodi Antonelli, Phillip G. Febbo, Pinchas Cohen, Mark W. Dewhirst, Salvatore V. Pizzo, Stephen J. Freedland

Research output: Contribution to journalArticle

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Abstract

BACKGROUND Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm3. Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day - HR 1.53, P = 0.04; 100 mg/kg/day - HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted. Prostate 73: 754-762, 2013. © 2012 Wiley Periodicals, Inc.

Original languageEnglish (US)
Pages (from-to)754-762
Number of pages9
JournalProstate
Volume73
Issue number7
DOIs
StatePublished - May 2013

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SCID Mice
Heterografts
Prostatic Neoplasms
Cell Line
Survival
resveratrol
Neoplasms
Insulin-Like Growth Factor Binding Protein 2
Gene Expression
beta Catenin
Insulin-Like Growth Factor I
Western Diet
Prostate
Up-Regulation
Enzyme-Linked Immunosorbent Assay
Fats
Carbohydrates

Keywords

  • beta-catenin
  • E2F3
  • IGF-1
  • prostate cancer
  • resveratrol
  • xenograft

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways. / Klink, Joseph C.; Tewari, Alok K.; Masko, Elizabeth M.; Antonelli, Jodi; Febbo, Phillip G.; Cohen, Pinchas; Dewhirst, Mark W.; Pizzo, Salvatore V.; Freedland, Stephen J.

In: Prostate, Vol. 73, No. 7, 05.2013, p. 754-762.

Research output: Contribution to journalArticle

Klink, Joseph C. ; Tewari, Alok K. ; Masko, Elizabeth M. ; Antonelli, Jodi ; Febbo, Phillip G. ; Cohen, Pinchas ; Dewhirst, Mark W. ; Pizzo, Salvatore V. ; Freedland, Stephen J. / Resveratrol worsens survival in SCID mice with prostate cancer xenografts in a cell-line specific manner, through paradoxical effects on oncogenic pathways. In: Prostate. 2013 ; Vol. 73, No. 7. pp. 754-762.
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abstract = "BACKGROUND Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS SCID mice were fed Western diet (40{\%} fat, 44{\%} carbohydrate, 16{\%} protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm3. Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day - HR 1.53, P = 0.04; 100 mg/kg/day - HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted. Prostate 73: 754-762, 2013. {\circledC} 2012 Wiley Periodicals, Inc.",
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AU - Klink, Joseph C.

AU - Tewari, Alok K.

AU - Masko, Elizabeth M.

AU - Antonelli, Jodi

AU - Febbo, Phillip G.

AU - Cohen, Pinchas

AU - Dewhirst, Mark W.

AU - Pizzo, Salvatore V.

AU - Freedland, Stephen J.

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N2 - BACKGROUND Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm3. Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day - HR 1.53, P = 0.04; 100 mg/kg/day - HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted. Prostate 73: 754-762, 2013. © 2012 Wiley Periodicals, Inc.

AB - BACKGROUND Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts. METHODS SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm3. Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays. RESULTS Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day - HR 1.53, P = 0.04; 100 mg/kg/day - HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors. CONCLUSION Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted. Prostate 73: 754-762, 2013. © 2012 Wiley Periodicals, Inc.

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KW - E2F3

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KW - resveratrol

KW - xenograft

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