• Transl Res · May 2019

    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, H Carlo Maurer, Kenneth P Olive, Katie L Bailey, Bradley E Britigan, and Sushil Kumar.
    • Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: maher.abdalla@unmc.edu.
    • Transl Res. 2019 May 1; 207: 566956-69.

    AbstractPancreatic 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.Copyright © 2019 Elsevier Inc. All rights reserved.

      Pubmed     Copy Citation     Plaintext  

      Add institutional full text...

    Notes

     
    Knowledge, pearl, summary or comment to share?
    300 characters remaining
    help        
    You can also include formatting, links, images and footnotes in your notes
    • Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.
    • Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.
    • Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.
    • Links can be included with: [my link to pubmed](http://pubmed.com)
    • Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")
    • For footnotes use [^1](This is a footnote.) inline.
    • Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..

    hide…