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Brain Behav Immun. 2018 Oct;73:294-309. doi: 10.1016/j.bbi.2018.05.014. Epub 2018 May 22.

Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome.

Author information

1
Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Israel.
2
Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, M.D. Anderson Cancer Center at University of Texas, Huston, TX, USA.
3
Department of Surgery and Transplantation, Sheba Medical Center, Ramat Gan, Israel.
4
Department of Surgery, Rabin Medical Center, Beilinson Hospital, Petach-Tikva, Israel.
5
Department of Surgery, Kaplan Medical Center, Rehovot, Israel.
6
Department of Pathology, Sheba Medical Center, Ramat Gan, Israel.
7
Department of Medicine, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
8
Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Israel. Electronic address: Shamgar@post.tau.ac.il.

Abstract

Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.

KEYWORDS:

Beta-adrenergic; Cancer; Cytokines; Etodolac; Inflammation; Ki-67; Metastasis; NFκB; NSAID; PCMCs; Perioperative; Propranolol; Stress; Transcription factors

PMID:
29800703
DOI:
10.1016/j.bbi.2018.05.014
[Indexed for MEDLINE]

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