DETANONOate is a potent chemo\radio-sensitizing agent in colon and colorectal cancers as assessed in in vitro and in vivo established tumor xenografts

Sergio Huerta, Xiaohuan Gao, Benjamin Bonavida

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Nitric oxide (NO) is a novel cancer therapeutic, and NO donors provide a unique advantage in the study of the properties of NO as an antineoplastic agent because they exhibit novel anti-tumor sensitizing abilities and reverse resistance to cytotoxic therapies. We present evidence on the enhancement by NO, used in combination with chemotherapy, of drug-induced apoptosis in colorectal cancer cells and NO-mediated regression of tumor xenografts resistant to conventional chemo- and radiotherapeutic interventions. Treatment with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETANONOate) sensitized SW620 metastatic CRC cells to cisplatin (CDDP)-induced apoptosis. Nude mice bearing SW620 xenografts treated with CDDP and DETANONOate demonstrated a 36% reduction in tumor load compared with control, and this was associated with an up-regulation of the expression of the apoptosis-inducing factor (AIF). Similarly, in models of rectal cancer, pretreating radio-resistant HT-29 colorectal cancer cells with DETANONOate for 16 h prior to ionizing radiation resulted in a significant reduction in colony formation (47%) compared with DETANONOate treatment alone. In vivo, SCID mice bearing HT-29 xenografts and treated with irradiation, DETANONOate, or a combination showed tumor growth reduction by 32.5% following the combination treatment. In vitro, the sensitizing activity of DETANONOate was associated with an up-regulation of p21, p27, and BAX, with a concomitant decrease in Bcl-2 expression in DETANONOate-pretreated HT-29 cells compared with controls. Altogether, these results demonstrate that DETANONOate is a potent chemo-radio-sensitizer in colorectal cancer cells that are resistant to conventional chemo- and radiotherapies.

Original languageEnglish (US)
Pages (from-to)281-295
Number of pages15
JournalForum on Immunopathological Diseases and Therapeutics
Volume1
Issue number4
DOIs
StatePublished - 2010

Fingerprint

Radio
Heterografts
Colonic Neoplasms
Tumors
Colorectal Neoplasms
Neoplasms
Nitric Oxide
Bearings (structural)
Chemotherapy
Cells
Up-Regulation
Apoptosis Inducing Factor
Apoptosis
Therapeutics
HT29 Cells
SCID Mice
Nitric Oxide Donors
In Vitro Techniques
2,2'-(hydroxynitrosohydrazono)bis-ethanamine
Ionizing radiation

Keywords

  • AIF
  • BAX
  • Ionizing radiation
  • Pathological complete response
  • Rectal cancer

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Biochemistry
  • Biotechnology

Cite this

@article{87a01bddefdf4e4ba340ddbaac03dba7,
title = "DETANONOate is a potent chemo\radio-sensitizing agent in colon and colorectal cancers as assessed in in vitro and in vivo established tumor xenografts",
abstract = "Nitric oxide (NO) is a novel cancer therapeutic, and NO donors provide a unique advantage in the study of the properties of NO as an antineoplastic agent because they exhibit novel anti-tumor sensitizing abilities and reverse resistance to cytotoxic therapies. We present evidence on the enhancement by NO, used in combination with chemotherapy, of drug-induced apoptosis in colorectal cancer cells and NO-mediated regression of tumor xenografts resistant to conventional chemo- and radiotherapeutic interventions. Treatment with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETANONOate) sensitized SW620 metastatic CRC cells to cisplatin (CDDP)-induced apoptosis. Nude mice bearing SW620 xenografts treated with CDDP and DETANONOate demonstrated a 36{\%} reduction in tumor load compared with control, and this was associated with an up-regulation of the expression of the apoptosis-inducing factor (AIF). Similarly, in models of rectal cancer, pretreating radio-resistant HT-29 colorectal cancer cells with DETANONOate for 16 h prior to ionizing radiation resulted in a significant reduction in colony formation (47{\%}) compared with DETANONOate treatment alone. In vivo, SCID mice bearing HT-29 xenografts and treated with irradiation, DETANONOate, or a combination showed tumor growth reduction by 32.5{\%} following the combination treatment. In vitro, the sensitizing activity of DETANONOate was associated with an up-regulation of p21, p27, and BAX, with a concomitant decrease in Bcl-2 expression in DETANONOate-pretreated HT-29 cells compared with controls. Altogether, these results demonstrate that DETANONOate is a potent chemo-radio-sensitizer in colorectal cancer cells that are resistant to conventional chemo- and radiotherapies.",
keywords = "AIF, BAX, Ionizing radiation, Pathological complete response, Rectal cancer",
author = "Sergio Huerta and Xiaohuan Gao and Benjamin Bonavida",
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volume = "1",
pages = "281--295",
journal = "Forum on Immunopathological Diseases and Therapeutics",
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TY - JOUR

T1 - DETANONOate is a potent chemo\radio-sensitizing agent in colon and colorectal cancers as assessed in in vitro and in vivo established tumor xenografts

AU - Huerta, Sergio

AU - Gao, Xiaohuan

AU - Bonavida, Benjamin

PY - 2010

Y1 - 2010

N2 - Nitric oxide (NO) is a novel cancer therapeutic, and NO donors provide a unique advantage in the study of the properties of NO as an antineoplastic agent because they exhibit novel anti-tumor sensitizing abilities and reverse resistance to cytotoxic therapies. We present evidence on the enhancement by NO, used in combination with chemotherapy, of drug-induced apoptosis in colorectal cancer cells and NO-mediated regression of tumor xenografts resistant to conventional chemo- and radiotherapeutic interventions. Treatment with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETANONOate) sensitized SW620 metastatic CRC cells to cisplatin (CDDP)-induced apoptosis. Nude mice bearing SW620 xenografts treated with CDDP and DETANONOate demonstrated a 36% reduction in tumor load compared with control, and this was associated with an up-regulation of the expression of the apoptosis-inducing factor (AIF). Similarly, in models of rectal cancer, pretreating radio-resistant HT-29 colorectal cancer cells with DETANONOate for 16 h prior to ionizing radiation resulted in a significant reduction in colony formation (47%) compared with DETANONOate treatment alone. In vivo, SCID mice bearing HT-29 xenografts and treated with irradiation, DETANONOate, or a combination showed tumor growth reduction by 32.5% following the combination treatment. In vitro, the sensitizing activity of DETANONOate was associated with an up-regulation of p21, p27, and BAX, with a concomitant decrease in Bcl-2 expression in DETANONOate-pretreated HT-29 cells compared with controls. Altogether, these results demonstrate that DETANONOate is a potent chemo-radio-sensitizer in colorectal cancer cells that are resistant to conventional chemo- and radiotherapies.

AB - Nitric oxide (NO) is a novel cancer therapeutic, and NO donors provide a unique advantage in the study of the properties of NO as an antineoplastic agent because they exhibit novel anti-tumor sensitizing abilities and reverse resistance to cytotoxic therapies. We present evidence on the enhancement by NO, used in combination with chemotherapy, of drug-induced apoptosis in colorectal cancer cells and NO-mediated regression of tumor xenografts resistant to conventional chemo- and radiotherapeutic interventions. Treatment with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETANONOate) sensitized SW620 metastatic CRC cells to cisplatin (CDDP)-induced apoptosis. Nude mice bearing SW620 xenografts treated with CDDP and DETANONOate demonstrated a 36% reduction in tumor load compared with control, and this was associated with an up-regulation of the expression of the apoptosis-inducing factor (AIF). Similarly, in models of rectal cancer, pretreating radio-resistant HT-29 colorectal cancer cells with DETANONOate for 16 h prior to ionizing radiation resulted in a significant reduction in colony formation (47%) compared with DETANONOate treatment alone. In vivo, SCID mice bearing HT-29 xenografts and treated with irradiation, DETANONOate, or a combination showed tumor growth reduction by 32.5% following the combination treatment. In vitro, the sensitizing activity of DETANONOate was associated with an up-regulation of p21, p27, and BAX, with a concomitant decrease in Bcl-2 expression in DETANONOate-pretreated HT-29 cells compared with controls. Altogether, these results demonstrate that DETANONOate is a potent chemo-radio-sensitizer in colorectal cancer cells that are resistant to conventional chemo- and radiotherapies.

KW - AIF

KW - BAX

KW - Ionizing radiation

KW - Pathological complete response

KW - Rectal cancer

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U2 - 10.1615/ForumImmunDisTher.v1.i4.30

DO - 10.1615/ForumImmunDisTher.v1.i4.30

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VL - 1

SP - 281

EP - 295

JO - Forum on Immunopathological Diseases and Therapeutics

JF - Forum on Immunopathological Diseases and Therapeutics

SN - 2151-8017

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