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Perioperative COX2 and β‐adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial
Abstract
Background: Preclinical studies have implicated excess release of catecholamines and prostaglandins in the mediation of prometastatic processes during surgical treatment of cancer. In this study, we tested the combined perioperative blockade of these pathways in patients with colorectal cancer (CRC). Methods: In a randomized, double‐blind, placebo‐controlled biomarker trial involving 34 patients, the β‐blocker propranolol and the COX2‐inhibitor etodolac were administered for 20 perioperative days, starting 5 days before surgery. Excised tumors were subjected to whole genome messenger RNA profiling and transcriptional control pathway analyses. Results: Drugs were well‐tolerated, with minor complications in both the treatment group and the placebo group. Treatment resulted in a significant improvement ( P < .05) of tumor molecular markers of malignant and metastatic potential, including 1) reduced epithelial‐to‐mesenchymal transition, 2) reduced tumor infiltrating CD14 + monocytes and CD19 + B cells, and 3) increased tumor infiltrating CD56 + natural killer cells. Transcriptional activity analyses indicated a favorable drug impact on 12 of 19 a priori hypothesized CRC‐related transcription factors, including the GATA, STAT, and EGR families as well as the CREB family that mediates the gene regulatory impact of β‐adrenergic– and prostaglandin‐signaling. Alterations observed in these transcriptional activities were previously associated with improved long‐term clinical outcomes. Three‐year recurrence rates were assessed for long‐term safety analyses. An intent‐to‐treat analysis revealed that recurrence rates were 12.5% (2/16) in the treatment group and 33.3% (6/18) in the placebo group ( P = .239), and in protocol‐compliant patients, recurrence rates were 0% (0/11) in the treatment group and 29.4% (5/17) in the placebo group ( P = .054). Conclusions: The favorable biomarker impacts and clinical outcomes provide a rationale for future randomized placebo‐controlled trials in larger samples to assess the effects of perioperative propranolol/etodolac treatment on oncological clinical outcomes.
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“In a similar trial by Haldar et al., in 34 patients with colorectal cancer there was also a markedly reduction of recurrences in the treatment group with propranolol and etodolac (12.5%) compared to the placebo group (33.3%) [22].”
From Pancreatic resection with perioperative drug repurposing of propranolol and etodolac – the phase II randomized controlled PROSPER trial (2025) · cites this paper as [22]
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RetractedPharmacological interventions targeting β-adrenoceptors in colorectal cancer: an evolving paradigm
Ghosn, A., Bassam, K., Zein, M. A., Nasser, S. A., Pintus, G., & Eid, A. H. (2025) · Inflammopharmacology · doi:10.1007/s10787-025-01925-5 · Cited by 3
“Contextually, β-AR blockade, particularly targeting the β 1 - AR and β 2 -AR subtypes, has been linked with favorable clinical benefits in patients with CRC (Haldar et al. 2020).”
InfluentialChung, Y. E., Paik, E. S., Kim, M., Kim, N., Lim, S., Seo, J., Choi, C. H., Kim, T., Lee, J., & Lee, Y.-Y. (2025) · Cancers · doi:10.3390/cancers17213422 · Cited by 3
“…and COX-2 blockade around the time of surgery favorably alters tumor and immune biomarkers (reduced EMT signatures, favorable immune infiltrates), with promising signals toward lower recurrence in protocol-adherent patients [23] and consistent phase-II data in early-stage breast cancer [24].”
Li, Z., Liao, J.-L., Luo, M.-R., Fang, S.-J., Huang, W., & Zhang, D.-Y. (2025) · World Journal of Clinical Oncology · doi:10.5306/wjco.v16.i10.108954 · Cited by 4
Jiang, H., Zhang, G., Sun, W., Zhang, H., Zhang, S., & Wang, H. (2026) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2026.01.010 · Cited by 3
Sakis, N., Sorski, L., Asraf, E., Ricon‐Becker, I., Shaashua, L., Haldar, R., Shvalbo, B. B., Shabat-Simon, M., Gutman, M., Nissan, A., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1823113 · Cited by 3
“…including (i) decreased EMT, (ii) decreased tumor-infiltrating CD14 + monocytes, (iii) favorably modified GATA, STAT, and EGR transcription factor activity, and (iv) increased tumor-infiltrating Natural Killer cells in CRC patients (Haldar et al., 2020; Shaashua et al., 2017; Hiller et al., 2020).”
InfluentialSelf-citationChen, Q., Li, M., Chen, J., Huang, Z. J., Chen, X., Zhao, H., & Cai, J. (2022) · BMC Cancer · doi:10.1186/s12885-022-10009-4 · Cited by 3
Liu, L., Li, J., Lai, J., & Shi, S. (2023) · World Journal of Gastrointestinal Surgery · doi:10.4240/wjgs.v15.i4.520 · Cited by 3
Beta‐Blockers and Cutaneous Melanoma Outcomes: A Systematic Review and Random‐Effects Meta‐Analysis
Muller, N., Tan, S. X., Vipulaguna, N., Zhou, C., Hughes, M. C. B., Soyer, H. P., von Schuckmann, L. A., & Khosrotehrani, K. (2025) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.13225 · Cited by 4
“This distinction is consistent with prognostic studies on beta-blocker use in ovarian, breast, and colorectal cancer (Yap et al. 2018; Haldar et al. 2020).”
Advancing the human right to health in cancer care through drug repurposing strategies
Sakis, N., Slone, M., Michaan, N., & Ben‐Eliyahu, S. (2025) · International Journal for Equity in Health · doi:10.1186/s12939-025-02598-w · Cited by 2
Self-citationPerioperative Immunomodulation and Cancer Recurrence
Villa, J. F., Ramirez, M. F., Anderson, J. L., Sikora, A. G., Sharma, J., & Cata, J. P. (2026) · International Anesthesiology Clinics · doi:10.1097/aia.0000000000000509 · Cited by 2
Norepinephrine promotes colorectal cancer liver metastasis via mechanisms dependent on Kupffer cells
Li, Y., Zhi, J., Li, X., Liu, J., Yuan, N., Zhao, J., Wang, B., & Jia, Y. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116449 · Cited by 2
Parsa, S., Sarkani, E. O., Chaleshtori, Z. M., Darash, S., Fotros, N., Iraj, K. M., Ehsani, F. Z., Naeini, Y. M., Yahyazadeh, S., Fatehpour, M., et al. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116454 · Cited by 2
Redefining surgical oncology: active immune microenvironment modulation beyond tumor resection
谭家雄, Zhang, Y., Wang, J., Xia, Y., Pan, Y., & Zhao, Q. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116521 · Cited by 3
The Impact of Anaesthesia Drugs and Techniques on Cancer Recurrence
Cata, J. P., & Guran, E. (2022) · Türk anesteziyoloji ve reanimasyon derneği dergisi · doi:10.5152/tjar.2022.22091 · Cited by 1
Selvaraj, K. J., Damian, D. L., Lyons, J. G., Wilmott, J. S., Ferguson, P. M., McGrady, M., Bartula, I., Lo, S. N., Scolyer, R. A., Ferguson, A. L., et al. (2026) · PLoS ONE · doi:10.1371/journal.pone.0339476 · Cited by 1
Bao, Q., Chen, H., Wu, J., Wang, Y., Chen, X., Lin, Z., Xu, Y., & Chen, J. (2026) · APOPTOSIS · doi:10.1007/s10495-026-02347-6 · Cited by 1
“The review by Haldar et al. systematically summarizes the multifaceted roles of β-AR signaling in the lung cancer microenvi - ronment, including the promotion of EMT, which confers migratory capacity and stem-like properties—both closely linked to resistance [185].”
Social Genomics and Cancer: Neural Regulation of the Cancer Genome
Knight, J. M., & Cole, S. W. (2022) · Springer eBooks · doi:10.1007/978-3-030-85702-8_21 · Cited by 1
Self-citationThe Renin-Angiotensin System and Cancer
Koh, S. P., Kilmister, E. J., Wickremesekera, A., Munro, M. J., Gray, C., & Tan, S. T. (2023) · Advances in biochemistry in health and disease · doi:10.1007/978-3-031-23621-1_15 · Cited by 1
Lowe, M., Sukhatme, V. V., & Sukhatme, V. P. (2020) · Cancer · doi:10.1002/cncr.32949
Metadata
- Authors
- Haldar, R., Ricon‐Becker, I., Radin, A., Gutman, M., Cole, S. W., Zmora, O., & Ben‐Eliyahu, S.
- Affiliations
- Tel Aviv University (IL)
- University of California, Los Angeles (US)
- Sheba Medical Center (IL)
- Assaf Harofeh Medical Center (IL)
- Corresponding author
- Ben‐Eliyahu, Shamgar
- Venue
- Cancer
- Publisher
- Wiley
- Published
- 2020-06-13
- Volume
- 126
- Issue
- 17
- Pages
- 3991-4001
- ISSN
- 0008-543X (ISSN-L)
- 1097-0142
- OpenAlex
- W3035075055
- Cited by
- 122
- References
- 47
- Citations by year
- 2026: 24 · 2025: 17 · 2024: 13 · 2023: 22 · 2022: 25 · 2021: 16 · 2020: 5
- FWCI
- 12.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation (1406/10)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- colorectal cancer, perioperative therapy, propranolol, etodolac, COX-2 inhibition, beta-adrenergic blockade, catecholamines, prostaglandins, metastasis, epithelial-mesenchymal transition, tumor-infiltrating immune cells, natural killer cells, CD14+ monocytes, CD19+ B cells, tumor recurrence, gene expression profiling, transcription factors, GATA, STAT, EGR, CREB
- MeSH terms
- Adrenergic beta-Antagonists, Adult, Aged, Female, Humans, Immunity, Innate, Inflammation, Killer Cells, Natural, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Recurrence, Local, Biomarkers, Tumor, Colorectal Neoplasms, Signal Transduction, Cell Line, Tumor, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors
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