Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition

Maher Y Abdalla, Iman M Ahmad, Satyanarayana Rachagani, Kasturi Banerjee, Christopher M. Thompson, Hans C. Maurer, Kenneth P. Olive, Katie L. Bailey, Bradley E. Britigan, Sushil Kumar

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and has one of the worst prognoses leading to a meager 5-year survival rate of ∼8%. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC due to poor tumor perfusion and hypoxia-induced resistance. Hypoxia reprograms the gene expression profile and upregulates the expression of multiple genes including heme oxygenase-1 (HO-1), which provide survival advantage to PDAC cells. However, the relationships between HO-1, hypoxia, and response to chemotherapy is unclear. Our results showed that hypoxia upregulates the expression of HO-1 in PDAC cells, and HO-1 inhibition using the HO-1 inhibitors zinc protoporphyrin, tin protoporphyrin IX (SnPP), and HO-1 knockout using CRISPR/Cas9 suppresses the proliferation of PDAC cells under hypoxia and sensitize them to gemcitabine under in vitro conditions. Treating orthotopic tumors with SnPP, or SnPP in combination with gemcitabine, significantly reduced the weight of pancreatic tumors (P < 0.05), decreased metastasis and improved the efficacy of gemcitabine treatment (P < 0.05). Mechanistically, inhibition of HO-1 increased the production of reactive oxygen species as demonstrated by increased dihydroethidium, and Mitosox, disrupted glutathione cycle, and enhanced apoptosis. There was significant increase in cleaved caspase-3 staining in tumors after combined treatment with SnPP and gemcitabine comparing to control or gemcitabine alone. In addition, inhibiting HO-1 reduced expression of stemness markers (CD133, and CD44) as compared to control or gemcitabine. Overall, our study may present a novel therapeutic regimen that might be adopted for the treatment of PDAC patients.

Original languageEnglish (US)
Pages (from-to)56-69
Number of pages14
JournalTranslational Research
Volume207
DOIs
StatePublished - May 2019

Fingerprint

gemcitabine
Heme Oxygenase-1
Pancreatic Neoplasms
Cells
Adenocarcinoma
Tumors
Chemotherapy
Therapeutics
Up-Regulation
Clustered Regularly Interspaced Short Palindromic Repeats
Drug Therapy
Cell Hypoxia
Neoplasms
Hypoxia
Tumor Burden
Transcriptome
Gene expression
Caspase 3
Glutathione
Reactive Oxygen Species

Keywords

  • Gemcitabine
  • Heme oxygenase-1 (HO-1)
  • Pancreatic ductal adenocarcinoma (PDAC)
  • SnPP
  • ZnPP

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical
  • Physiology (medical)

Cite this

Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition. / Abdalla, Maher Y; Ahmad, Iman M; Rachagani, Satyanarayana; Banerjee, Kasturi; Thompson, Christopher M.; Maurer, Hans C.; Olive, Kenneth P.; Bailey, Katie L.; Britigan, Bradley E.; Kumar, Sushil.

In: Translational Research, Vol. 207, 05.2019, p. 56-69.

Research output: Contribution to journalArticle

Abdalla, Maher Y ; Ahmad, Iman M ; Rachagani, Satyanarayana ; Banerjee, Kasturi ; Thompson, Christopher M. ; Maurer, Hans C. ; Olive, Kenneth P. ; Bailey, Katie L. ; Britigan, Bradley E. ; Kumar, Sushil. / Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition. In: Translational Research. 2019 ; Vol. 207. pp. 56-69.
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abstract = "Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and has one of the worst prognoses leading to a meager 5-year survival rate of ∼8{\%}. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC due to poor tumor perfusion and hypoxia-induced resistance. Hypoxia reprograms the gene expression profile and upregulates the expression of multiple genes including heme oxygenase-1 (HO-1), which provide survival advantage to PDAC cells. However, the relationships between HO-1, hypoxia, and response to chemotherapy is unclear. Our results showed that hypoxia upregulates the expression of HO-1 in PDAC cells, and HO-1 inhibition using the HO-1 inhibitors zinc protoporphyrin, tin protoporphyrin IX (SnPP), and HO-1 knockout using CRISPR/Cas9 suppresses the proliferation of PDAC cells under hypoxia and sensitize them to gemcitabine under in vitro conditions. Treating orthotopic tumors with SnPP, or SnPP in combination with gemcitabine, significantly reduced the weight of pancreatic tumors (P < 0.05), decreased metastasis and improved the efficacy of gemcitabine treatment (P < 0.05). Mechanistically, inhibition of HO-1 increased the production of reactive oxygen species as demonstrated by increased dihydroethidium, and Mitosox, disrupted glutathione cycle, and enhanced apoptosis. There was significant increase in cleaved caspase-3 staining in tumors after combined treatment with SnPP and gemcitabine comparing to control or gemcitabine alone. In addition, inhibiting HO-1 reduced expression of stemness markers (CD133, and CD44) as compared to control or gemcitabine. Overall, our study may present a novel therapeutic regimen that might be adopted for the treatment of PDAC patients.",
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AU - Ahmad, Iman M

AU - Rachagani, Satyanarayana

AU - Banerjee, Kasturi

AU - Thompson, Christopher M.

AU - Maurer, Hans C.

AU - Olive, Kenneth P.

AU - Bailey, Katie L.

AU - Britigan, Bradley E.

AU - Kumar, Sushil

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AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and has one of the worst prognoses leading to a meager 5-year survival rate of ∼8%. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC due to poor tumor perfusion and hypoxia-induced resistance. Hypoxia reprograms the gene expression profile and upregulates the expression of multiple genes including heme oxygenase-1 (HO-1), which provide survival advantage to PDAC cells. However, the relationships between HO-1, hypoxia, and response to chemotherapy is unclear. Our results showed that hypoxia upregulates the expression of HO-1 in PDAC cells, and HO-1 inhibition using the HO-1 inhibitors zinc protoporphyrin, tin protoporphyrin IX (SnPP), and HO-1 knockout using CRISPR/Cas9 suppresses the proliferation of PDAC cells under hypoxia and sensitize them to gemcitabine under in vitro conditions. Treating orthotopic tumors with SnPP, or SnPP in combination with gemcitabine, significantly reduced the weight of pancreatic tumors (P < 0.05), decreased metastasis and improved the efficacy of gemcitabine treatment (P < 0.05). Mechanistically, inhibition of HO-1 increased the production of reactive oxygen species as demonstrated by increased dihydroethidium, and Mitosox, disrupted glutathione cycle, and enhanced apoptosis. There was significant increase in cleaved caspase-3 staining in tumors after combined treatment with SnPP and gemcitabine comparing to control or gemcitabine alone. In addition, inhibiting HO-1 reduced expression of stemness markers (CD133, and CD44) as compared to control or gemcitabine. Overall, our study may present a novel therapeutic regimen that might be adopted for the treatment of PDAC patients.

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