The cutaneous squamous cell carcinoma (cSCC) is the second most frequent skin cancer in white ethnic populations worldwide,, and even if most of the cases are easily cured by surgical removal, this cancer remains the cause of the majority of non melanoma skin cancer (NMSC) deaths. This is due to “high-risk SCCs”, which are associated with significant metastasis, morbidity, and death,. Among the main cause of cSCC, the DNA damage by ultraviolet (UV) radiation exposure is the most common, since it causes the deregulation of important signaling pathways that are involved on cell cycle, apoptosis, DNA repair and cell differentiation-. Other risk factors to cSCC promotion are immunosuppression, human papilloma virus (HPV) infection-, genetic disorders and smoking. Sporadically, cSCC can be also associated with non-healing wounds/scarring, or chronic lesions preceded by chronic inflammatory processes,.
Usually, in situ cSCC may be controlled by different interventions, including electrodessication and curettage, topical therapy, cryotherapy, and photodynamic therapy; however, since these treatments are not appropriate for invasive cSCC, surgical excision is usually indicated. The surgical procedure creates wounds that could be small, superficial, and amenable to primary closure, but often they can be large, deep, and extensive needing more complex closure and covering. Specifically scalp injuries, due to its low elasticity, can be devastating and can require significantly more extensive surgeries, concerning both the number and complexity. Consequently, we believe that an effective therapeutic strategy could be to control the extension of the lesion before its excision aspiring for a less invasive surgery with less devastating wounds.
Multiple intracellular signal transduction pathways that are involved events such as cellular replication, inflammation, angiogenesis, apoptosis, cell motility and trafficking, activation of tumor- associated viruses, DNA damage repair, cellular immune response and epithelial–mesenchymal transition (reviewed by Coelho M et al) are regulated through interactions of α- and β-adrenoceptors (AR) and Catecholamine (CA) neurotransmitters. Tumor cells may express β-AR, and the involvement of β-adrenergic signaling in the progression of malignant diseases has been increasingly recognized-. The use of beta-blocker therapy can reduce the incidence of prostate cancer and improve the prognosis of patients with breast and hepatocellular cancer. The expression of β-AR in the A431 cSCC human cells was described in 1987 by Kashles and Levitzki, which leads us to believe that cSCC proliferation may be controlled by using β-AR-blockers. Thus, we hypothesized that the topical application of a β-AR-blocker over the tumor lesion may decrease/restrain its extension before the surgical excision becoming an adjuvant\therapy against cSCC. The topical application of β-AR-blocker (timolol- and propranolol) was already described on infantile hemangioma, with no collateral effects.
Recent evidence has shown that non-selective β-blocking (±)-Propranolol Hydrochloride, improved the progression-free survival of breast cancer patients, and reduced the risk of developing head and neck, prostate, esophagus, stomach, and colon cancers. It is known that the (±)-Propranolol Hydrochloride anti-cancer activity is due to its ability to inhibit the mitochondrial metabolism, which can increase the cell glycolytic activity resulting in elevated metabolism and switch towards aerobic glycolysis, which could stimulate the tumor progression and drug resistance. However, its anti-cancer activity as a single agent was demonstrated to be limited.
Hence, based on the well-known Warbur effect, cancer cells boost glucose uptake and conversion into lactate in the presence of high oxygen tension, exploiting the aerobic glycolysis, we suggested the combination of propranolol with the glucose analog 2-Deoxy-D-glucose (2-DG) aiming to improve its antiproliferative effect. 2DG is a well-known antidiabetic drug, which by competition can inhibits glucose uptake, blocking the first critical step of glucose metabolism and the mitochondrial respiration, inducing a metabolic stress. 2DG increases autophagy, a ubiquitous cellular catabolic process that under conditions of protracted stresses suppresses tumorigenesis. 2DG treatment alone does not significantly induce cancer cells death, but it may use with specific agents or to exert a synergistic therapeutic action.
To confirm these hypotheses, we performed in vitro assays using the human A431 cSCC cell line. We demonstrated that the addition of 2DG to (±)-Propranolol Hydrochloride therapy can improve its effect on A431 cells metabolism and proliferation.