Abstract
BackgroundBreast cancer in women is one of the leading causes of cancer mortality worldwide, and curative therapy is the main focus of clinical treatment. Anesthetic-analgesic techniques might alter stress responses and immunity and thereby influence outcomes in cancer patients. This study investigated the effect of tramadol on breast cancer progression and metastasis.MethodsThe effects of tramadol on two different subtypes of human breast adenocarcinoma cell lines, MDA-MB-231 and MCF-7, were studied with regard to cell growth, migration, colony formation and invasion and normoxic or hypoxic microenvironment for the expression of hypoxia-inducible factor-1α, reactive oxygen species, epithelial-mesenchymal transition related and cyclin-related proteins. The co-administration of tramadol and doxorubicin was studied to determine whether the effective doxorubicin dose might be reduced in combination with tramadol.ResultsThe results showed that tramadol inhibited cell growth at concentrations more than 0.5 and more than 1.0 mg/mL in MDA-MB-231 and MCF-7 cells, respectively. Additionally, cell migration, colony formation and invasion were inhibited in a dose-dependent manner by tramadol in both cell lines. The combination of tramadol and doxorubicin induced synergistic effects in MDA-MD-231 cells and, with specific dosage combinations in MCF-7 cells.ConclusionsTramadol may regulate epithelial-mesenchymal transition and possess cytotoxic effects in breast cancer cells. Tramadol inhibits the progression of breast cancer cells and might be a candidate for combination therapy, especially for triple-negative breast cancer, and is a promising treatment strategy for breast cancer.
Highlights
The results showed that the tramadol half-maximal inhibition concentrations (IC50) were determined as 0.8 and 1.1 mg/mL for MDA-MB-231 and MCF-7, respectively
Tramadol, which is used for acute pain management after breast cancer surgery, is associated with lower risk of tolerance, dependence and respiratory depression. [20, 21] Recent preclinical and clinical studies have shown that tramadol possesses immunostimulatory effects that through NK cell activation and lymphocyte proliferation [22, 23]; tramadol reduces the risk of lung metastasis in rats
(24) Tramadol confers an antitumorigenic effect against proliferation, migration and invasion in lung cancer cells by upregulating the phosphatase and tensin homolog and interfering with phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling [25] and by downregulating the a2receptor in breast cancer cells (MDA-MB-231) [14]; our results are consistent with the abovementioned findings
Summary
Breast cancer in women, which contributed to 11.7% of the global cancer incidence and 6.9% of global cancer mortality in 2020 (GLOBOCAN report), has surpassed lung cancer as the commonest malignancy and is one of the top five causes of cancer mortality. [1] Surgical resection is one of the major treatment options for breast cancer, and perioperative surgical and anesthetic interventions may alter the stress responses and immunity and could even modulate the tumor microenvironment of patients. [2] The mechanisms through which anesthetic-analgesic techniques influence breast cancer outcomes have increasingly garnered attention the results of research have been inconsistent. [3,4,5,6,7,8,9,10,11]Tramadol is a centrally acting analgesic that is widely accepted in the treatment of moderate postoperative pain. [12] Piñero and colleagues [13] reported that b-adrenoceptor agonists and a2adrenoceptor antagonists can effectively suppress breast cancer cell proliferation and tumor growth via the inhibition of extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation in an animal model. [1] Surgical resection is one of the major treatment options for breast cancer, and perioperative surgical and anesthetic interventions may alter the stress responses and immunity and could even modulate the tumor microenvironment of patients. [12] Piñero and colleagues [13] reported that b-adrenoceptor agonists and a2adrenoceptor antagonists can effectively suppress breast cancer cell proliferation and tumor growth via the inhibition of extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation in an animal model. Tramadol inactivates a2-adrenoceptor signaling and inhibits the proliferation, migration and invasion of breast cancer cells. This study was conducted with an aim to ascertain the effects of tramadol on cell growth, migration and invasion as well as on EMT in relation to breast cancer recurrence and metastasis. This study investigated the effect of tramadol on breast cancer progression and metastasis
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