Beta-Adrenergic Antagonist – Cyclooxygenase-2 Inhibitor
A study published in the Journal of Immunology suggests that the combined blockade of excess release of catecholamines (CAs) and prostaglandins (PGs) in cancer patients undergoing tumor excision might improve survival rates and prevent cancer recurrence.
The surgical procedure, a common step in the treatment of most solid cancers, has long been suspected to facilitate the metastatic process, and numerous mechanisms have been implicated.
The study in the Journal of Immunology by Ariella Glasner and colleagues promotes the clinical testing of a new approach for reducing long-term cancer recurrence: blocking excessive perioperative paracrine and neuroendocrine stress responses, and specifically a combined blockade of excess release of CAs and PGs in the perioperative period in cancer patients undergoing tumor excision.
Such an approach has not been tested clinically thus far.
In this study, the authors report that in mice, blocking beta-adrenoreceptors with propranolol and simultaneously inhibiting PG synthesis with etodolac significantly improves recurrence-free survival rates following 3LL or B16 primary tumor excision. These tumors, like most human cancers are poorly immunogenic, expressing no MHC-II and low levels of MHC-I.
Thus, the combination of propranolol and etodolac, but neither drug alone, significantly and markedly improved survival rates in both tumor models. Surgery markedly reduced NK cytotoxicity and NK cell expression of Fas ligand and CD11a, reduced all circulating lymphocyte-subtype concentrations, and increased corticosterone levels. Propranolol and etodolac administration counteracted these perturbations.
Of note, only the combined administration of beta-adrenergic antagonist and cyclooxygenase-2 inhibitor had a significant prophylactic effect in the survival studies.
Of note, only the combined administration of beta-adrenergic antagonist and cyclooxygenase-2 inhibitor had a significant prophylactic effect in the survival studies.
A possible explanation for this synergism is that during the postoperative period both PG and CA levels are high, and each factor alone can interfere with various immunologic components and pathways and induce suppression of cell-mediated immunity.
This study also indicates that the immediate postoperative period is critical for determining long-term tumor recurrence rates, and that clinical interventions during this time may have substantial long-term benefits.
The authors suggest that drug regimen used in this study may be even more efficient if initiated a few days before surgery, because etodolac could reduce PGs release by primary tumors; propranolol could reduce anxiety and antagonize the excess release of CAs owing to preoperative physiologic and psychologic stress responses.
Overall this can attenuate preoperative suppression of cellular immunity in cancer patients awaiting surgery.
SOURCE: J Immunol 2010, 184: 2449
Updates
A 2017 study by Lee Shaashua et al. represents the first clinical trial to test the efficacy of a combined perioperative treatment with a β-blocker and a COX-2 inhibitor in breast cancer patients.
This study reports that the drug treatment
- decreased epithelial-to-mesenchymal transition,
- reduced activity of pro-metastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and
- decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells.
- The drug treatment also significantly abrogated presurgical increases in serum interleukin-6 (IL-6) and C-reactive protein levels
- And abrogated perioperative declines in stimulated interleukin-12 and interferon-gamma production, abrogated postoperative mobilization of CD16− “classical” monocytes, and enhanced expression of CD11a on circulating natural killer cells.
In conclusion, this first clinical trial of perioperative treatment with a COX-2 inhibitor and a β-adrenergic antagonist in early stage breast cancer finds a favorable safety profile and favorable impact on multiple tumor and circulating biomarkers associated with cancer progression and metastasis.
A 2018 study by Rita Haldar et al. reports the results from a randomized two-arm placebo-controlled phase-II biomarker clinical trial tested the combined perioperative use of propranolol and etodolac in breast cancer (BC) patients. This includes the immunological results from four blood samples taken perioperatively (twice before and twice after surgeryand histological analysis of the excised tumor tissue. Thus, blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4).
The study aimed to test the hypotheses that drug treatment would reduce stress and immune-related inflammatory responses, identify potential mediating molecular mechanisms, and study indices of anti-metastatic immunity and molecular biomarkers of long-term cancer outcomes.
The investigators found that 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.
The authors concluded that the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.
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