Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer

Shrey Modi, Devika Kir, Bhuwan Giri, Kaustav Majumder, Nivedita Arora, Vikas Dudeja, Sulagna Banerjee, Ashok Saluja

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Introduction: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Methods: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0–10 μM), low-dose triptolide (50 nM), or a combination of both for 24–48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Results: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Conclusions: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)13-24
Number of pages12
JournalJournal of Gastrointestinal Surgery
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

oxaliplatin
Pancreatic Neoplasms
DNA Repair
Down-Regulation
DNA Damage
Neoplasms
Cell Death
14-O-phosphonooxymethyltriptolide

Keywords

  • DNA damage pancreatic cancer
  • Minnelide
  • NER
  • Oxaliplatin
  • Triptolide

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

Cite this

Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer. / Modi, Shrey; Kir, Devika; Giri, Bhuwan; Majumder, Kaustav; Arora, Nivedita; Dudeja, Vikas; Banerjee, Sulagna; Saluja, Ashok.

In: Journal of Gastrointestinal Surgery, Vol. 20, No. 1, 01.01.2016, p. 13-24.

Research output: Contribution to journalArticle

@article{5852eb6b4a0f41cc9a14d72fcf6e829d,
title = "Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer",
abstract = "Introduction: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Methods: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0–10 μM), low-dose triptolide (50 nM), or a combination of both for 24–48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Results: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Conclusions: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer.",
keywords = "DNA damage pancreatic cancer, Minnelide, NER, Oxaliplatin, Triptolide",
author = "Shrey Modi and Devika Kir and Bhuwan Giri and Kaustav Majumder and Nivedita Arora and Vikas Dudeja and Sulagna Banerjee and Ashok Saluja",
year = "2016",
month = "1",
day = "1",
doi = "10.1007/s11605-015-3000-3",
language = "English (US)",
volume = "20",
pages = "13--24",
journal = "Journal of Gastrointestinal Surgery",
issn = "1091-255X",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer

AU - Modi, Shrey

AU - Kir, Devika

AU - Giri, Bhuwan

AU - Majumder, Kaustav

AU - Arora, Nivedita

AU - Dudeja, Vikas

AU - Banerjee, Sulagna

AU - Saluja, Ashok

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Introduction: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Methods: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0–10 μM), low-dose triptolide (50 nM), or a combination of both for 24–48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Results: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Conclusions: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer.

AB - Introduction: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Methods: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0–10 μM), low-dose triptolide (50 nM), or a combination of both for 24–48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Results: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Conclusions: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer.

KW - DNA damage pancreatic cancer

KW - Minnelide

KW - NER

KW - Oxaliplatin

KW - Triptolide

UR - http://www.scopus.com/inward/record.url?scp=84952976373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84952976373&partnerID=8YFLogxK

U2 - 10.1007/s11605-015-3000-3

DO - 10.1007/s11605-015-3000-3

M3 - Article

VL - 20

SP - 13

EP - 24

JO - Journal of Gastrointestinal Surgery

JF - Journal of Gastrointestinal Surgery

SN - 1091-255X

IS - 1

ER -