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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, H Carlo; Olive, Kenneth P; Bailey, Katie L; Britigan, Bradley E; Kumar, Sushil.
Afiliación
  • Abdalla MY; Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. Electronic address: maher.abdalla@unmc.edu.
  • Ahmad IM; Department of Medical Imaging and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, Nebraska.
  • Rachagani S; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
  • Banerjee K; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
  • Thompson CM; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
  • Maurer HC; Departments of Medicine and Pathology & Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
  • Olive KP; Departments of Medicine and Pathology & Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
  • Bailey KL; Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
  • Britigan BE; Research Service, VA Medical Center, Nebraska/Western Iowa, Omaha, Nebraska; Department of Internal Medicine; University of Nebraska Medical Center, Omaha, Nebraska.
  • Kumar S; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
Transl Res ; 207: 56-69, 2019 05.
Article en En | MEDLINE | ID: mdl-30653942
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Desoxicitidina / Hemo-Oxigenasa 1 Límite: Animals / Female / Humans / Male Idioma: En Revista: Transl Res Asunto de la revista: MEDICINA / TECNICAS E PROCEDIMENTOS DE LABORATORIO Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Desoxicitidina / Hemo-Oxigenasa 1 Límite: Animals / Female / Humans / Male Idioma: En Revista: Transl Res Asunto de la revista: MEDICINA / TECNICAS E PROCEDIMENTOS DE LABORATORIO Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos