Vol.:(0123456789) 1 3 Cancer Chemotherapy and Pharmacology (2020) 86:681–686 https://doi.org/10.1007/s00280-020-04149-2 SHORT COMMUNICATION Beta‑adrenergic blocker inhibits oral carcinogenesis and reduces tumor invasion Heitor Pinhata Cecilio 1  · Vitor Bonetti Valente 1  · Karla Marcila Pereira 1  · Giseli Mitsuy Kayahara 1,2  · Cristiane Furuse 2  · Éder Ricardo Biasoli 1,2  · Glauco Issamu Miyahara 1,2  · Sandra Helena Penha Oliveira 3  · Daniel Galera Bernabé 1,2 Received: 1 July 2020 / Accepted: 16 September 2020 / Published online: 27 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Purpose Beta-adrenergic signaling can influence cancer progression and the use of beta blockers as adjuvant drugs in oncologic patients has been suggested. However, the involvement of beta-adrenergic blockers in tumorigenesis is poorly understood. This study investigated the action of beta-adrenergic blocker propranolol on tumor onset using a preclinical model of chemically induced oral cancer. Methods Thirty-two male Wistar rats were subjected to daily subcutaneous injection of beta-blocker propranolol (10 mg/ kg; SubQ), while another 32 rats received only a PBS injection (sham group). One week after starting propranolol treatment, all rats were submitted to chemical induction of oral carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). After 16 weeks, they were assessed for occurrence of oral squamous cell carcinoma (OSCC), in addition to measurement of tumor volume and thickness, and tissue levels of cytokines IL-6, TNF-alpha and IL-10 in the tumor microenvironment. Results Propranolol treatment reduced the occurrence of OSCC by 31%, 95% CI ( − 127, 216). Beta-adrenergic blocker significantly decreased thickness of OSCC when compared with PBS. Rats treated with propranolol exhibited a lower tumor volume when compared with control rats, but this result did not reach statistical significance. Tumors from propranolol-treated rats exhibited reduced concentrations of pro-inflammatory cytokines IL-6 and TNF-α. There was no difference in the IL-10 levels between tumors from propranolol- and sham-treated rats. Conclusion Beta-adrenergic signaling may be one of the mechanisms associated with chemically induced oral carcinogenesis. Keywords Oral cancer · Carcinogenesis · Cancer progression · Propranolol · Beta-adrenergic antagonists Introduction Clinical studies have shown that the chronic use of the non-selective beta blockers can affect cancer development [1–5]. Long-term beta-blocker therapy may reduce the incidence of prostate cancer [1] and improve the prognosis of patients with breast [2] and hepatocellular [3] cancer. Recent evidence has shown that propranolol, a non-selec- tive beta blocker, improved the progression-free survival of breast cancer patients [4]. In a large population-based study, propranolol use reduced the risk of developing head and neck, prostate, esophagus, stomach, and colon can- cers [5]. Propranolol treatment can affect the occurrence and progression of cancer through the inhibition of beta- adrenergic signaling activated by catecholamines [6–10]. In a previous study, we showed that the use of propranolol inhibited the proliferation of oral cancer cells induced by norepinephrine and this effect was dependent on the acti- vation of beta-adrenergic receptors [6]. Propranolol treat- ment can also increase the expression of anti-inflammatory cytokine IL-10 [11]. In addition, beta blocker can pre- vent DNA damage and malignant transformation of cells induced by the catecholamines and other beta-adrenergic * Daniel Galera Bernabé daniel.bernabe@unesp.br 1 Psychoneuroimmunology Laboratory, Psychosomatic Research Center, Oral Oncology Center, São Paulo State University (Unesp), School of Dentistry, 1193 José Bonifácio St, Araçatuba, São Paulo 15050-015, Brazil 2 Department of Diagnosis and Surgery, São Paulo State University (Unesp), School of Dentistry, 1193 José Bonifácio St, Araçatuba, São Paulo 15050-015, Brazil 3 Immunopharmacology Laboratory, Department of Basic Sciences, São Paulo State University (Unesp), School of Dentistry, 1193 José Bonifácio St, Araçatuba, São Paulo 15050-015, Brazil