Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment
Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both...
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| Language: | English |
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Elsevier
2025-04-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325000701 |
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| author | Ramia J. Salloom Dania Z. Sahtout Iman M. Ahmad Maher Y. Abdalla |
| author_facet | Ramia J. Salloom Dania Z. Sahtout Iman M. Ahmad Maher Y. Abdalla |
| author_sort | Ramia J. Salloom |
| collection | DOAJ |
| description | Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4+ and CD8+ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes. |
| format | Article |
| id | doaj-art-7375eda86d9b449eb03c5bf30664301f |
| institution | DOAJ |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-7375eda86d9b449eb03c5bf30664301f2025-08-20T02:46:29ZengElsevierTranslational Oncology1936-52332025-04-015410233910.1016/j.tranon.2025.102339Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatmentRamia J. Salloom0Dania Z. Sahtout1Iman M. Ahmad2Maher Y. Abdalla3Department of Pathology, Microbiology, and Immunology, USADepartment of Pathology, Microbiology, and Immunology, USADepartment of Clinical, Diagnostics, and Therapeutic Sciences, University of Nebraska Medical Center, Omaha, NE, USADepartment of Pathology, Microbiology, and Immunology, USA; Corresponding author.Prostate cancer (PC) remains a leading cause of morbidity and mortality among men worldwide, highlighting the need for novel therapeutic strategies. Our study investigates the therapeutic potential of targeting the heme degradation pathway through heme oxygenase-1 (HO-1) inhibition in PC. Using both in vitro and in vivo models, we explored the effects of combining HO-1 inhibition with chemotherapy, represented by docetaxel (Doc), on tumor growth and immune infiltration. In vitro experiments demonstrated that HO-1 inhibition, as well as HO-1 knockout (KO), significantly reduced tumor cell proliferation and enhanced chemosensitivity in RM-1 cells. Additionally, U937 cells co-cultured with HO-1 KO cells shifted cell polarization toward an M1 phenotype. In vivo, the combined treatment of the HO-1 inhibitor, tin protoporphyrin (SnPP), with Doc significantly enhanced anti-tumor efficacy in mouse models compared to chemotherapy or SnPP alone. This combination therapy not only reduced Ki67 expression and increased CC3 expression in tumor tissues but also shifted macrophage polarization toward an M1 phenotype and enhanced CD4+ and CD8+ T cells infiltration, indicating an augmented immune response. Further investigation using macrophage-specific HO-1 knockout mice revealed a direct role of HO-1 inhibition in driving macrophage polarization, confirming its involvement in promoting the shift toward an M1 phenotype. Although this response was significant, it was more robust with systemic HO-1 inhibition. Our findings indicate that HO-1 inhibition can potentiate the effects of chemotherapy, offering a promising avenue for improving PC treatment outcomes.http://www.sciencedirect.com/science/article/pii/S1936523325000701Heme oxygenase-1 (HO-1)Prostate cancer (PC)ZnPPSnPPand Docetaxel (Doc) |
| spellingShingle | Ramia J. Salloom Dania Z. Sahtout Iman M. Ahmad Maher Y. Abdalla Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment Translational Oncology Heme oxygenase-1 (HO-1) Prostate cancer (PC) ZnPP SnPP and Docetaxel (Doc) |
| title | Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment |
| title_full | Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment |
| title_fullStr | Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment |
| title_full_unstemmed | Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment |
| title_short | Synergistic effects of HO-1 inhibition and chemotherapy on tumor proliferation and immune infiltration: An in vitro and in vivo approach to enhancing prostate cancer treatment |
| title_sort | synergistic effects of ho 1 inhibition and chemotherapy on tumor proliferation and immune infiltration an in vitro and in vivo approach to enhancing prostate cancer treatment |
| topic | Heme oxygenase-1 (HO-1) Prostate cancer (PC) ZnPP SnPP and Docetaxel (Doc) |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325000701 |
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