Improving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a β-Adrenergic Antagonist and a Cyclooxygenase-2 Inhibitor

Abstract

Clinical practice does not consider perioperative paracrine and neuroendocrine stress responses as risk factors for cancer recurrence, although recent animal studies provided supportive evidence. Suggested mechanisms include the effects of stress-hormones on tumor cells and on host physiology. In this study, in mice undergoing primary tumor excision, we tested the survival-enhancing potential of perioperative blockade of catecholamines and prostaglandins, and studied potential mediating mechanisms. C57BL/6J mice were inoculated intrafootpad with syngeneic B16F10.9-melanoma or Lewis lung carcinoma, and the paw was amputated when a developing tumor exceeded 100 μl. The clinically used β-adrenergic antagonist propranolol, and/or the cyclooxygenase-2 inhibitor etodolac, were administered once before amputation, and recurrence-free survival was monitored. In different studies, NK cytotoxicity, leukocytes' molecular functional markers, and vascular endothelial growth factor secretion by tumor cells were studied in the context of surgery and drug treatments. The findings indicated that the combination of propranolol and etodolac, but neither drug alone, significantly and markedly improved survival rates in both tumor models, and was as effective as established immunostimulatory agents (IL-12 and polyinosinic-polycytiylic acid). 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. B16 and 3LL secreted vascular endothelial growth factor in vitro, but secretion was not affected by catecholamine agonists, prostaglandins, corticosterone, propranolol, or etodolac. Overall, propranolol and etodolac administration, which could be applied perioperatively in most cancer patients with minimal risk and low cost, has counteracted several immunologic and endocrinologic perturbations and improved recurrence-free survival rates in mice undergoing primary tumor excision.

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

“…Interestingly, in many cancers, metastases are more likely to form only after the primary tumor is removed. This is caused by increased dissemination of tumor cells during the removal of the primary tumor (20), decreased levels of anti-angiogenic factors, local and systemic increases in proangiogenic and growth factors (e.g., VEGF) (21), blood loss (22), and the suppression of cell- mediated immunity (following the surgery) (23,24). Also, the primary tumor is known to secrete immunosuppressive factors such as PGE 2 , IL-10 and TGF-b, which increase the likelihood of tumor cells to stay close to the initial mass of the primary tumor.…”

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

“…Preclinical studies have demonstrated that β-adrenergic signaling can regulate multiple fundamental biological processes underlying the progression and metastasis of tumors, including the promotion of inflammation [72][73][74], angiogenesis [75][76][77][78], migration [79], invasion [80,81] and resistance to programmed cell death [82][83][84][85]. Some evidence suggests that the stimulation of β-adrenergic signaling can also inhibit DNA damage repair and the cellular immune response [86,87] and promote surgery-induced metastasis [88,89]. Figure 5 β-adrenergic signaling modulates multiple cellular processes in tumor progression and metastasis.…”

New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma

“…Propranolol, a non-selective b-adrenergic blocking agent, is used predominantly for the treatment for hypertension, cardiac arrhythmias, coronary artery disease, thyrotoxicosis, migraine headache, and a number of other conditions such as psychiatric diseases (Emilien and Maloteaux 1998;Frohlich 1977;Featherstone 1983;Lee et al 1982). In recent years, the data obtained from meta-analysis and in vitro and in vivo experimental studies showed that beta-receptor antagonists inhibit tumor proliferation and metastasis in breast, stomach, skin, and colon cancers (Masur et al 2001;Benjamin et al 2010;Slotkin et al 2000;Glasner et al 2010;Benish et al 2008;Algazi et al 2004;Park et al 1995). In vitro, the antiangiogenic biological activity of propranolol was also shown to inhibit human brain microvascular endothelial cell tubulogenesis (Annabi et al 2009).…”