Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis

Lavanya Reddivari, Venkata Charepalli, Sridhar Radhakrishnan, Ramakrishna Vadde, Ryan Elias, Joshua D. Lambert, Jairam K.P. Vanamala

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Methods: We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. Results: RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear ß-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocationof ß-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/ß-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. Conclusion: The suppression of Wnt/ß-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.

Original languageEnglish (US)
Article number278
JournalBMC complementary and alternative medicine
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2016

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Grape Seed Extract
Neoplastic Stem Cells
Vitis
Colonic Neoplasms
Rodentia
Colon
Carcinogenesis
Catenins
Sulindac
Apoptosis
In Vitro Techniques
Azoxymethane
resveratrol
Wnt Signaling Pathway
Cyclin D1
Tumor Suppressor Genes
Small Interfering RNA
Neoplasms
Cell Proliferation
Radiation

All Science Journal Classification (ASJC) codes

  • Complementary and alternative medicine

Cite this

Reddivari, Lavanya ; Charepalli, Venkata ; Radhakrishnan, Sridhar ; Vadde, Ramakrishna ; Elias, Ryan ; Lambert, Joshua D. ; Vanamala, Jairam K.P. / Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. In: BMC complementary and alternative medicine. 2016 ; Vol. 16, No. 1.
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title = "Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis",
abstract = "Background: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Methods: We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. Results: RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear {\ss}-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocationof {\ss}-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/{\ss}-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. Conclusion: The suppression of Wnt/{\ss}-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.",
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Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. / Reddivari, Lavanya; Charepalli, Venkata; Radhakrishnan, Sridhar; Vadde, Ramakrishna; Elias, Ryan; Lambert, Joshua D.; Vanamala, Jairam K.P.

In: BMC complementary and alternative medicine, Vol. 16, No. 1, 278, 01.01.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis

AU - Reddivari, Lavanya

AU - Charepalli, Venkata

AU - Radhakrishnan, Sridhar

AU - Vadde, Ramakrishna

AU - Elias, Ryan

AU - Lambert, Joshua D.

AU - Vanamala, Jairam K.P.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Methods: We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. Results: RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear ß-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocationof ß-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/ß-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. Conclusion: The suppression of Wnt/ß-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.

AB - Background: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. Methods: We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. Results: RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear ß-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocationof ß-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/ß-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial-mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. Conclusion: The suppression of Wnt/ß-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy.

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