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 a marked reduction of recurrences in the treatment group with propranolol and etodolac (12.5%) compared to the placebo group (33.3%).
“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]
Cites
Siegel, R. L., Miller, K. D., & Jemal, A. (2019) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21551 · Cited by 20,160 · see citing works
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684 · see citing works
Integrating liquid biopsies into the management of cancer
Siravegna, G., Marsoni, S., Siena, S., & Bardelli, A. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.14 · Cited by 1,941 · see citing works
Steptoe, A., Hamer, M., & Chida, Y. (2007) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2007.03.011 · Cited by 1,278 · see citing works
Sympathetic nervous system regulation of the tumour microenvironment
Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A., & Sood, A. K. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3978 · Cited by 576 · see citing works
Self-citationPerioperative events influence cancer recurrence risk after surgery
Hiller, J. G., Perry, N. J., Poulogiannis, G., Riedel, B., & Sloan, E. K. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.194 · Cited by 556 · see citing works
COX-2: A Molecular Target for Colorectal Cancer Prevention
Brown, J. R., & DuBois, R. N. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.09.051 · Cited by 529 · see citing works
Exploiting the critical perioperative period to improve long-term cancer outcomes
Horowitz, M., Neeman, E., Sharon, E., & Ben-Eliyahu, S. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.224 · Cited by 487 · see citing works
Self-citationQuantitative evidence for early metastatic seeding in colorectal cancer
Hu, Z., Ding, J., Ma, Z., Sun, R., Seoane, J. A., Shaffer, J. S., Suarez, C. J., Berghoff, A. S., Cremolini, C., Falcone, A., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0423-x · Cited by 480 · see citing works
Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery
Reinert, T., Schøler, L. V., Thomsen, R., Tobiasen, H., Vang, S., Nordentoft, I., Lamy, P., Kannerup, A.-S., Mortensen, F. V., Stribolt, K., et al. (2015) · Gut · doi:10.1136/gutjnl-2014-308859 · Cited by 464 · see citing works
Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer
Erreni, M., Mantovani, A., & Allavena, P. (2010) · Cancer Microenvironment · doi:10.1007/s12307-010-0052-5 · Cited by 324 · see citing works
Buvanendran, A., Kroin, J. S., Berger, R. A., Hallab, N. J., Saha, C., Negrescu, C., Moric, M. M., Caicedo, M. S., & Tuman, K. J. (2006) · Anesthesiology · doi:10.1097/00000542-200603000-00005 · Cited by 290 · see citing works
Shaashua, L., Shabat-Simon, M., Haldar, R., Matzner, P., Zmora, O., Shabtai, M., Sharon, E., Allweis, T. M., Barshack, I., Hayman, L., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0152 · Cited by 282 · see citing works
Self-citationMacrophages as Key Drivers of Cancer Progression and Metastasis
Nielsen, S. R., & Schmid, M. C. (2017) · Mediators of Inflammation · doi:10.1155/2017/9624760 · Cited by 281 · see citing works
Benish, M., Bartal, I., Goldfarb, Y., Levi, B., Avraham, R., Raz, A., & Ben-Eliyahu, S. (2008) · Annals of Surgical Oncology · doi:10.1245/s10434-008-9890-5 · Cited by 281 · see citing works
Self-citationTumor Budding is a Strong and Reproducible Prognostic Marker in T3N0 Colorectal Cancer
Wang, L. M., Kevans, D., Mulcahy, H. E., O'Sullivan, J. N., Fennelly, D. W., Hyland, J. M., O’Donoghue, D. P., & Sheahan, K. D. (2008) · The American Journal of Surgical Pathology · doi:10.1097/pas.0b013e318184cd55 · Cited by 280 · see citing works
Improving Postoperative Immune Status and Resistance to Cancer Metastasis
Goldfarb, Y., Sorski, L., Benish, M., Levi, B. Z., Melamed, R., & Ben‐Eliyahu, S. (2011) · Annals of Surgery · doi:10.1097/sla.0b013e318211d7b5 · Cited by 262 · see citing works
Self-citationReversal of Tumor-Induced Immunosuppression: A New Approach to Cancer Therapy
Wojtowicz‐Praga, S. (1997) · Journal of Immunotherapy · doi:10.1097/00002371-199705000-00001 · Cited by 242 · see citing works
Glasner, A., Avraham, R., Rosenne, E., Benish, M., Zmora, O., Shemer, S., Meiboom, H., & Ben‐Eliyahu, S. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903301 · Cited by 239 · see citing works
Self-citationHost Factors and Cancer Progression: Biobehavioral Signaling Pathways and Interventions
Lutgendorf, S. K., Sood, A. K., & Antoni, M. H. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.9357 · Cited by 238 · see citing works
Shah, S., Divekar, A., Hilchey, S. P., Cho, H.-M., Newman, C. L., Shin, S.-U., Nechushtan, H., Challita-Eid, P. M., Segal, B. M., Yi, K. H., et al. (2005) · International Journal of Cancer · doi:10.1002/ijc.21177 · Cited by 227 · see citing works
Hiller, J. G., Cole, S. W., Crone, E. M., Byrne, D. J., Shackleford, D. M., Pang, J.-M. B., Henderson, M. A., Nightingale, S. S., Ho, K. M., Myles, P. S., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-2641 · Cited by 223 · see citing works
Self-citationImmune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis
Menon, A. G., Rhijn, C. M. J., Morreau, H., Putter, H., Tollenaar, R. A. �. �., van de Velde, C. J. �., Fleuren, G. J., & Kuppen, P. J. K. (2004) · Laboratory Investigation · doi:10.1038/labinvest.3700055 · Cited by 216 · see citing works
Survival Following Recurrence in Stage II and III Colon Cancer: Findings From the ACCENT Data Set
O’Connell, M. J., Campbell, M. E., Goldberg, R. M., Grothey, A. F., Seitz, J. F., Benedetti, J., André, T., Haller, D. G., & Sargent, D. J. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.8261 · Cited by 213 · see citing works
Májek, O., Gondos, Á., Jansen, L., Emrich, K., Holleczek, B., Katalinic, A., Nennecke, A., Eberle, A., Brenner, H., & the GEKID Cancer Survival Working Group (2013) · PLoS ONE · doi:10.1371/journal.pone.0068077 · Cited by 196 · see citing works
Expression-based monitoring of transcription factor activity: the TELiS database
Cole, S. W., Yan, W., Galic, Z., Arevalo, J., & Zack, J. A. (2005) · Bioinformatics · doi:10.1093/bioinformatics/bti038 · Cited by 185 · see citing works
Self-citationNeil, J. R., JOHNSON, K. M., Nemenoff, R. A., & Schiemann, W. P. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn202 · Cited by 158 · see citing works
Sex differences in epidemiological, clinical and pathological characteristics of colorectal cancer
Koo, J. H., & Leong, R. W. L. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2009.05992.x · Cited by 138 · see citing works
Characterization of tumor-associated B-cell subsets in patients with colorectal cancer
Shimabukuro‐Vornhagen, A., Schlößer, H., Gryschok, L., Malcher, J., Wennhold, K., Garcia-Marquez, M. A., Herbold, T., Neuhaus, L. S., Becker, H., Fiedler, A., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1701 · Cited by 127 · see citing works
Neeman, E., Zmora, O., & Ben‐Eliyahu, S. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1087 · Cited by 113 · see citing works
Self-citationNatural killer cells infiltrating colorectal cancer and MHC class I expression
Sandel, M. H., Speetjens, F. M., Menon, A. G., Albertsson, P., Basse, P. H., Hokland, M., Nagelkerke, J. F., Tollenaar, R. A. E. M., van de Velde, C. J. �., & Kuppen, P. J. K. (2004) · Molecular Immunology · doi:10.1016/j.molimm.2004.07.039 · Cited by 107 · see citing works
Armaiz-Peña, G. N., González-Villasana, V., Nagaraja, A. S., Rodriguez‐Aguayo, C., Sadaoui, N. C., Stone, R. L., Matsuo, K., Dalton, H. J., Previs, R. A., Jennings, N. B., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.2887 · Cited by 105 · see citing works
Self-citationAugestad, K. M., Bakaki, P. M., Rose, J., Crawshaw, B. P., Lindsetmo, R. O., Dørum, L. M., Koroukian, S. M., & Delaney, C. P. (2015) · Cancer Epidemiology · doi:10.1016/j.canep.2015.07.009 · Cited by 102 · see citing works
Nakamura, T., Mitomi, H., Kikuchi, S., Ohtani, Y., & Sato, K. (2005) · PubMed · Cited by 92 · see citing works
Haldar, R., Shaashua, L., Lavon, H., Lyons, Y. A., Zmora, O., Sharon, E., Birnbaum, Y., Allweis, T. M., Sood, A. K., Barshack, I., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.05.014 · Cited by 88 · see citing works
Self-citationSorski, L., Melamed, R., Matzner, P., Lavon, H., Shaashua, L., Rosenne, E., & Ben-Eliyahu, S. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.05.017 · Cited by 85 · see citing works
Self-citationRicon, I., Hanalis‐Miller, T., Haldar, R., Jacoby, R., & Ben‐Eliyahu, S. (2019) · Cancer · doi:10.1002/cncr.31594 · Cited by 71 · see citing works
Self-citationDavis, F. M., Parsonage, M. T., Cabot, P. J., Parat, M., Thompson, E. W., Roberts‐Thomson, S. J., & Monteith, G. R. (2013) · Cancer Cell International · doi:10.1186/1475-2867-13-76 · Cited by 60 · see citing works
Adhim, Z., Matsuoka, T., Bito, T., Shigemura, K., Lee, K.-M., Kawabata, M., Fujisawa, M., Nibu, K., & Shirakawa, T. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.262 · Cited by 59 · see citing works
Norepinephrine induced epithelial–mesenchymal transition in HT-29 and A549 cells in vitro
Zhang, J., Deng, Y., Liu, J., Wang, Y., Yi, T., Huang, B., He, S., Zheng, B., & Jiang, Y. (2015) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-015-2044-9 · Cited by 57 · see citing works
Knight, J. M., Rizzo, J. D., Hari, P., Pasquini, M. C., Giles, K. E., D’Souza, A., Logan, B. R., Hamadani, M., Chhabra, S., Dhakal, B., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2019000765 · Cited by 53 · see citing works
Self-citationBates, R. C., Pursell, B. M., & Mercurio, A. M. (2007) · Cells Tissues Organs · doi:10.1159/000101300 · Cited by 48 · see citing works
Jang, T. J., Jeon, K. H., & Jung, K. H. (2009) · Yonsei Medical Journal · doi:10.3349/ymj.2009.50.6.818 · Cited by 43 · see citing works
Knight, J. M., Kerswill, S. A., Hari, P., Cole, S. W., Logan, B. R., D’Souza, A., Shah, N. N., Horowitz, M. M., Stolley, M. R., Sloan, E. K., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-4509-0 · Cited by 36 · see citing works
Self-citationHaldar, R., & Ben‐Eliyahu, S. (2018) · Future Oncology · doi:10.2217/fon-2017-0635 · Cited by 32 · see citing works
Self-citationDoes early metastatic seeding occur in colorectal cancer?
Magrì, A., & Bardelli, A. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0200-4 · Cited by 18 · see citing works
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Stress and cancer: mechanisms, significance and future directions
Eckerling, A., Ricon-Becker, I., Sorski, L., Sandbank, E., & Ben-Eliyahu, S. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-021-00395-5 · Cited by 348 · see citing works
Self-citationRole of adrenergic receptor signalling in neuroimmune communication
Chhatar, S., & Lal, G. (2021) · Current Research in Immunology · doi:10.1016/j.crimmu.2021.11.001 · Cited by 143 · see citing works
Neuro-immune crosstalk in cancer: mechanisms and therapeutic implications
Pu, T., Sun, J., Ren, G., & Li, H. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02241-8 · Cited by 140 · see citing works
“515 Although propranolol has shown promising effects in improving the TIME in these clinical studies, the impact on tumor recurrence rates and long-term survival outcomes of patients requires further observation and investigation.”
Stress and cancer: The mechanisms of immune dysregulation and management
Liu, Y., Tian, S., Ning, B., Huang, T., Li, Y., & Wei, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1032294 · Cited by 135 · see citing works
Neurobiology of Cancer: The Role of β-Adrenergic Receptor Signaling in Various Tumor Environments
Mravec, B., Horváthová, Ľ., & Hunáková, Ľ. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217958 · Cited by 114 · see citing works
Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
Hanahan, D., Michielin, O. A., & Pittet, M. J. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00761-z · Cited by 106 · see citing works
“A recent neoadjuvant clinical trial in colon cancer combining the β-blocker propranolol with a COX2 inhibitor has presented evidence of immunomodulation 268 , encouraging further investigation of β-blockers in combination with other immunomodulatory drugs.”
Carroll, J., Bower, J. E., & Ganz, P. A. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00580-3 · Cited by 79 · see citing works
Gillis, R. D., Botteri, E., Chang, A., Ziegler, A. I., Chung, N.-C., Pon, C. K., Shackleford, D. M., Andreassen, B. K., Halls, M. L., Baker, J. G., et al. (2021) · European Journal of Cancer · doi:10.1016/j.ejca.2021.01.029 · Cited by 76 · see citing works
“Recent clinical trials in patients with cancer have shown that propranolol reduced the risk of recurrence (21,22), and reduced biomarkers of cancer invasion and progression (23-25).”
BackgroundJennings, M. R., Munn, D. H., & Blazeck, J. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003013 · Cited by 63 · see citing works
Biobehavioral Pathways and Cancer Progression: Insights for Improving Well-Being and Cancer Outcomes
Chang, A., Sloan, E. K., Antoni, M. H., Knight, J. M., Telles, R., & Lutgendorf, S. K. (2022) · Integrative Cancer Therapies · doi:10.1177/15347354221096081 · Cited by 59 · see citing works
Yang, Y., Feng, M., Bai, L., Liao, W., Zhou, K., Zhang, M., Wu, Q., Wen, F., Lei, W., Zhang, P., et al. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-03065-0 · Cited by 52 · see citing works
“When EMT decreases in CRC, CD14 + monocytes and CD19 + B cells also decrease, and the tumor increases infiltration of CD56 + NK cells [34].”
BackgroundHanalis‐Miller, T., Nudelman, G., Ben‐Eliyahu, S., & Jacoby, R. (2022) · Frontiers in Psychology · doi:10.3389/fpsyg.2022.839065 · Cited by 52 · see citing works
“It has been shown in clinical studies that the preoperative period presents a “window of opportunity,” during which psychological and physiological stress responses can be moderated, potentially leading to improved immune function and even to reduced risks of cancer recurrence and metastasis (Antoni, 2003; Sood et al.…”
Self-citationBodywide ecological interventions on cancer
Kroemer, G., McQuade, J. L., Mérad, M., André, F., & Zitvogel, L. (2023) · Nature Medicine · doi:10.1038/s41591-022-02193-4 · Cited by 51 · see citing works
Neurobiology of cancer: Definition, historical overview, and clinical implications
Mravec, B. (2021) · Cancer Medicine · doi:10.1002/cam4.4488 · Cited by 52 · see citing works
Trial watch: beta-blockers in cancer therapy
Provost, K. C. L., Kepp, O., Kroemer, G., & Bezu, L. (2023) · OncoImmunology · doi:10.1080/2162402x.2023.2284486 · Cited by 45 · see citing works
Lin, Y., Liu, Y., Gao, Z., Jing, D., Bi, R., Cui, X., Cao, Q., Zhao, Q., Gao, R., Su, Y., et al. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.175718 · Cited by 43 · see citing works
The immunomodulatory effects of antihypertensive therapy: A review
Felkle, D., Jarczyński, M., Kaleta, K., Zięba, K., & Nazimek, K. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113287 · Cited by 38 · see citing works
Ben‐Eliyahu, S. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.06.004 · Cited by 38 · see citing works
Self-citationLocal anesthetics elicit immune-dependent anticancer effects
Bezu, L., Chuang, A. W., Sauvat, A., Humeau, J., Xie, W., Cerrato, G., Liu, P., Zhao, L., Zhang, S., Naour, J. L., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004151 · Cited by 37 · see citing works
Cancer catecholamine conundrum
Wackerhage, H., Christensen, J. F., Ilmer, M., von Luettichau, I., Renz, B. W., & Schönfelder, M. (2021) · Trends in cancer · doi:10.1016/j.trecan.2021.10.005 · Cited by 36 · see citing works
Chun, K., Kim, E., Kim, D., Song, N., Kim, W., Na, H., & Surh, Y. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116259 · Cited by 36 · see citing works
Hu, D., Shen, W., Gong, C., Cheng, F., Yao, C., Zhu, X., Wang, L., Zhao, C., & Zhu, S. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16320 · Cited by 34 · see citing works
Pellegata, N. S., Berriel Diaz, M., Rohm, M., & Herzig, S. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10058-y · Cited by 33 · see citing works
Lei, Y., Liao, F., Tian, Y., Wang, Y., Xia, F., & Wang, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1321176 · Cited by 35 · see citing works
Benjamin, D. J., Haslam, A., & Prasad, V. (2024) · Cancer Medicine · doi:10.1002/cam4.7049 · Cited by 30 · see citing works
Effect of chronic stress on tumorigenesis and development
Wang, C., Shen, Y., Ni, J., Hu, W., & Yang, Y. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04455-3 · Cited by 31 · see citing works
“Similar effect could also be found in patients with colorectal cancer [99, 100].”
ResultNeuroimmunology of cancer and associated symptomology
Scheff, N. N., & Saloman, J. L. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12496 · Cited by 33 · see citing works
Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials
Ioakeim‐Skoufa, I., Tobajas-Ramos, N., Menditto, E., Aza‐Pascual‐Salcedo, M., Miguel, A. G., Orlando, V., González‐Rubio, F., Fanlo, A., AZA, C. L., Ostasz, E., et al. (2023) · Cancers · doi:10.3390/cancers15112972 · Cited by 28 · see citing works
Murphy, O. C., Forget, P., Ma, D., & Buggy, D. J. (2023) · British Journal of Anaesthesia · doi:10.1016/j.bja.2023.07.027 · Cited by 27 · see citing works
β-adrenergic signaling blockade attenuates metastasis through activation of cytotoxic CD4 T cells
Fjæstad, K. Y., Johansen, A. Z., Linder, H., Baker, K. J., Schattefor, M., Czajkowski, N. K., Thorseth, M., Siersbæk, M. S., Kurzay, A., Perez-Penco, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65048-9 · Cited by 26 · see citing works
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Zhang, L., Yang, L., Jiang, S., & Yu, M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.766653 · Cited by 26 · see citing works
Hjazi, A. M., Nasir, F., Noor, R., Alsalamy, A., Zabibah, R. S., Romero‐Parra, R. M., Ullah, M. I., Mustafa, Y. F., Qasim, M. T., & Akram, S. V. (2023) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.154616 · Cited by 26 · see citing works
Awakening of Dormant Breast Cancer Cells in the Bone Marrow
Wieder, R. (2023) · Cancers · doi:10.3390/cancers15113021 · Cited by 24 · see citing works
Sandbank, E., Eckerling, A., Margalit, A., Sorski, L., & Ben‐Eliyahu, S. (2023) · Current Oncology · doi:10.3390/curroncol30080540 · Cited by 23 · see citing works
Self-citationChronic stress: a fourth etiology in tumorigenesis?
Khan, A., Song, M., & Dong, Z. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02402-x · Cited by 27 · see citing works
Sivanesan, S., Taskén, K. A., & Grytli, H. H. (2022) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.45230 · Cited by 24 · see citing works
Haldar, R., Berger, L. S., Rosenne, E., Radin, A. S., Eckerling, A., Sandbank, E., Sloan, E. K., Cole, S. W., & Ben‐Eliyahu, S. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.01.005 · Cited by 22 · see citing works
Self-citationAnaesthesia, analgesia, and cancer outcomes: time to think like oncologists?
Mincer, J. S., & Buggy, D. J. (2023) · British Journal of Anaesthesia · doi:10.1016/j.bja.2023.02.001 · Cited by 22 · see citing works
Anesthetic technique and cancer surgery outcomes
Dubowitz, J. A., Hiller, J. G., & Riedel, B. (2021) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000001002 · Cited by 21 · see citing works
Propranolol: A “Pick and Roll” Team Player in Benign Tumors and Cancer Therapies
Albiñana, V., Gallardo‐Vara, E., Casado‐Vela, J., Recio-Poveda, L., Botella, L. M., & Cuesta, Á. M. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11154539 · Cited by 21 · see citing works
“The results obtained in the above-mentioned trial (NCT00502684) on breast cancer [82,83] aimed to run a randomized, double-blind placebo-controlled two-arm interventional human trial (NCT03838029) [85] (Table S3).”
BackgroundO’Logbon, J., Tarantola, L., Williams, N. R., Mehta, S., Ahmed, A., & Davies, E. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-025-06262-2 · Cited by 22 · see citing works
Kwon, S. Y., Chun, K., Kil, H. K., Jung, N., Shin, H. A., Jang, J. Y., Choi, H. G., Oh, K. H., & Kim, M. (2021) · Oncology Letters · doi:10.3892/ol.2021.13065 · Cited by 20 · see citing works
Ricon‐Becker, I., Haldar, R., Simon, M. S., Gutman, M., Cole, S. W., Ben-Eliyahu, S., & Zmora, O. (2022) · European Journal of Surgical Oncology · doi:10.1016/j.ejso.2022.10.013 · Cited by 20 · see citing works
Self-citationHanalis‐Miller, T., Ricon‐Becker, I., Sakis, N., Trachtenberg, E., Ohayon, F., Wadhawker, S., Birnboim-Hazan, Y., Magen, A., Sharon, E., Tarrasch, R., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.02.009 · Cited by 19 · see citing works
Self-citationEffects of surgical trauma and intraoperative blood loss on tumour progression
Jin, X., Han, H., & Liang, Q. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1412367 · Cited by 19 · see citing works
Dynamic Interplay of Neuroendocrine Signaling and Immuno-surveillance in Tumor Niche Remodeling.
Xu, N., Bian, S.-Y., Lyu, P., He, X.-Y., & Zheng, W.-J. (2025) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2025.104958 · Cited by 20 · see citing works
Majerova, K., Zvarík, M., Ricon‐Becker, I., Hanalis‐Miller, T., Mikolášková, I., Bella, V., Mravec, B., & Hunáková, Ľ. (2022) · Scientific Reports · doi:10.1038/s41598-022-18865-7 · Cited by 15 · see citing works
Self-citationGarramona, F. T., Cunha, T. F., Vieira, J. S., Borges, G. S., Santos, G., de Castro, G., Ugrinowitsch, C., & Brum, P. C. (2023) · Lung Cancer Management · doi:10.2217/lmt-2023-0006 · Cited by 16 · see citing works
Farrugia, M. K., Ma, S. J., Mattson, D., Flaherty, L., Repasky, E. A., & Singh, A. K. (2020) · American Journal of Clinical Oncology · doi:10.1097/coc.0000000000000768 · Cited by 15 · see citing works
α‐Adrenoceptor stimulation attenuates melanoma growth in mice
Maccari, S., Buoncervello, M., Ascione, B., Stati, T., Macchia, D., Fidanza, S., Catalano, L., Matarrese, P., Gabriele, L., & Marano, G. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15731 · Cited by 15 · see citing works
Wang, J., Lu, S., Meng, Y., Fu, W., & Zhou, X. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175135 · Cited by 14 · see citing works
Hüttner, F. J., Klotz, R., Giese, N. A., Kong, B., Ahmed, A., Merz, D., Pöchmann, A., Burghaus, I., Hackert, T., Strobel, O., et al. (2025) · Langenbeck's Archives of Surgery · doi:10.1007/s00423-025-03735-3 · Cited by 15 · see citing works
“[22].”
Hüttner, F. J., Rooman, I., Bouche, G., Knebel, P., Hüsing, J., Mihaljevic, A. L., Hackert, T., Strobel, O., Büchler, M. W., & Diener, M. K. (2020) · BMJ Open · doi:10.1136/bmjopen-2020-040406 · Cited by 13 · see citing works
“19 The primary objective of this pilot trial will be to assess the safety of the combination therapy with propranolol and etodolac in the perioperative setting of pancreatic cancer surgery.”
Benefits of β-blockers in cancer treatment
Arif, M., Hardianti, M. S., Tyagita, N., & Safitri, A. H. (2022) · Oncology in Clinical Practice · doi:10.5603/ocp.2022.0016 · Cited by 13 · see citing works
Zhi, X., Kuang, X., & Li, J. (2022) · Cancers · doi:10.3390/cancers14143496 · Cited by 13 · see citing works
The role of COX-2 and its use as a therapeutic target in IBD and related colorectal cancer
Yang, L., Akanyibah, F. A., Yao, D., Jin, T., & Mao, F. (2025) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2025.110516 · Cited by 13 · see citing works
Miao, L., Lv, X., Huang, C., Li, P., Sun, Y., & Jiang, H. (2022) · PLoS ONE · doi:10.1371/journal.pone.0268473 · Cited by 12 · see citing works
Pharmacological Targeting of Epithelial-to-Mesenchymal Transition in Colorectal Cancer
Zafari, N., Velayati, M., Nassiri, M., Khazaei, M., Hassanian, S. M., Ferns, G. A., & Avan, A. (2022) · Current Pharmaceutical Design · doi:10.2174/1381612828666220728152350 · Cited by 13 · see citing works
Hu, T., Liu, C.-J., Yin, X., Tang, W., Yin, L., Bai, H., Liu, F., Wang, D., & Li, Y. (2023) · BMC Gastroenterology · doi:10.1186/s12876-023-02918-w · Cited by 11 · see citing works
Chang-qin, L., & Li, J. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104543 · Cited by 12 · see citing works
Rahmani, L. S., Abdelaatti, A., Wall, T. P., & Buggy, D. J. (2023) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000001261 · Cited by 10 · see citing works
Decoding the neuroimmune axis in colorectal cancer: From neural circuitry to therapeutic innovation
Li, Y., Yang, S.-Y., Zhang, Y.-R., & Wang, Y. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.04.001 · Cited by 10 · see citing works
Fan, L., Zeng, X., & Xu, G. (2023) · The Journal of Microbiology · doi:10.1007/s12275-022-00010-8 · Cited by 10 · see citing works
Blocking β2-AR and Inhibiting COX-2: A Promising Approach to Suppress OSCC Development
Huang, Z., Huang, L., Zhang, C., Chen, G., & Mai, H. (2024) · International Dental Journal · doi:10.1016/j.identj.2024.06.014 · Cited by 9 · see citing works
Therapeutic Perspectives for the Perioperative Period in Oral Squamous Cell Carcinoma (OSCC)
Galmiche, A., Saidak, Z., Bettoni, J., Ouendo, M., & Testelin, S. (2022) · Frontiers in Oral Health · doi:10.3389/froh.2021.764386 · Cited by 8 · see citing works
Anaesthetic Techniques and Strategies: Do They Influence Oncological Outcomes?
Murphy, L., Shaker, J., & Buggy, D. J. (2023) · Current Oncology · doi:10.3390/curroncol30060403 · Cited by 8 · see citing works
“The first is a 34 patient study which randomised patients with colorectal cancer to receive either propranolol and etodolac (a CoX-2 inhibitor) for 20 days perioperatively and beginning 5 days prior to surgery, or placebo [49].”
BackgroundNeurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer
Mravec, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22116115 · Cited by 8 · see citing works
The stress connection in cancer: the adrenergic fuelling of breast tumors
Albitre, Á., Reglero, C., González-Muñoz, T., & Penela, P. (2023) · Current Opinion in Physiology · doi:10.1016/j.cophys.2023.100720 · Cited by 8 · see citing works
Bezu, L., Forget, P., Hollmann, M. W., Parat, M., & Piegeler, T. (2024) · European Journal of Anaesthesiology · doi:10.1097/eja.0000000000002118 · Cited by 9 · see citing works
Chen, Y.-S., Liu, X.-S., & Guo, S.-W. (2021) · Reproductive Biomedicine Online · doi:10.1016/j.rbmo.2021.04.017 · Cited by 4 · see citing works
Hajibabaei, F., Movafagh, S. S., Salehzadeh, S., Derakhshandeh, K., & Gable, R. W. (2023) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2023.135857 · Cited by 7 · see citing works
R-etodolac is a more potent Wnt signaling inhibitor than enantiomer, S-etodolac
Roberts, J. S., Ma, C., Robertson, S. Y. T., Kang, S., Han, C. S., Deng, S. X., & Zheng, J. (2022) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2022.101231 · Cited by 7 · see citing works
Gerdin, A., Park, J., Häggström, J., Segelman, J., Matthiessen, P., Lydrup, M., Rutegård, M., on behalf of the RectoLeak Study Group, Sjöström, Ö. O., Staffan, M., et al. (2024) · International Journal of Colorectal Disease · doi:10.1007/s00384-024-04766-w · Cited by 6 · see citing works
Neuroimmune axis in gastrointestinal cancers: From mechanisms to therapeutic breakthrough
Zhang, Y., Chen, J., Zhou, Y., Jiang, Y., Hu, J., Liu, X., & Zhou, J. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116059 · Cited by 7 · see citing works
Farrugia, M. K., Long, M. D., Mattson, D., Flaherty, L., Dong, B., Gomez, E. C., Wei, L., Witkiewicz, A. K., Yao, S., Kaliński, P., et al. (2021) · Cancers · doi:10.3390/cancers13020205 · Cited by 6 · see citing works
“reported a trend towards improved distant failure and 3-year recurrence rates, as well as a more favorable gene expression profile in CRC patients using perioperative etodolac for 20 days in conjunction with propranolol [45].”
BackgroundZhang, Z., Weng, B.-S., Qiu, Y., Feng, H., Zhang, R., Zhang, J., Hu, Y., Yu, J., Li, G., & Liu, H. (2022) · Journal of Immunology Research · doi:10.1155/2022/7863480 · Cited by 6 · see citing works
“…fl ammatory therapy in breast and colorectal cancers, respectively, both fi nding that epithelial-to-mesenchymal transition was reduce and immune microenvironment was improved in transcriptome pro fi ling of the primary tumor, indicating lower three-year recurrence rates in colorectal cancer [11, 12].”
Return to intended oncological therapy following advanced ovarian cancer surgery: a narrative review
Tse, K. Y., Chu, M. M. Y., Chiu, J. W. K., Kwok, S. T., Irwin, M. G., Chan, A. H. Y., Ho, P., Cheng, C. P.-W., Ngu, S., & Chan, K. K. L. (2025) · Anaesthesia · doi:10.1111/anae.16521 · Cited by 5 · see citing works
Kubatka, P., Kapinová, A., Bojková, B., Joseph, V., Horňák, S., Kajo, K., Büsselberg, D., Šmejkal, K., Goncharenko, V., Mrazova, B., et al. (2026) · The EPMA Journal · doi:10.1007/s13167-026-00447-6 · Cited by 4 · see citing works
Role of the neurotransmitter-receptor pathway in T-cell tumor immunology and cancer immunotherapy
Fan, M., & Zhao, X. (2025) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2025216 · Cited by 4 · see citing works
Vonderhaar, E. P., Dwinell, M. B., & Craig, B. T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1202169 · Cited by 4 · see citing works
Anticancer and Anti-Inflammatory Mechanisms of NOSH-Aspirin and Its Biological Effects
Zhou, J., Zeng, W., Zeng, Y., Li, Y., Xiao, Z. Y., Zou, J., Peng, L., Xia, J., & Zeng, X. (2022) · Computational and Mathematical Methods in Medicine · doi:10.1155/2022/4463294 · Cited by 4 · see citing works
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 · see citing works
“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 · see citing works
“…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 3 · see citing works
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 · see citing works
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 · see citing works
“…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 · see citing works
Liu, L., Li, J., Lai, J., & Shi, S. (2023) · World Journal of Gastrointestinal Surgery · doi:10.4240/wjgs.v15.i4.520 · Cited by 3 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
Lowe, M., Sukhatme, V. V., & Sukhatme, V. P. (2020) · Cancer · doi:10.1002/cncr.32949
- 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
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Pharmacology › 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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