Potencial antineoplásico de antioxidantes e ação adjuvante do ácido gálico à radiação ionizante no carcinoma epidermoide de boca: uma revisão sistemática e estudo in vitro

Abstract

Oral squamous cell carcinoma (OSCC) is a disease commonly related to genetic and epigenetic changes, and to risk factors such as chronic smoking and alcoholism, being responsible for more than 90% of all oral malignancies. In individuals affected by OSCC, radiotherapy is an important therapeutic strategy to promote the death of neoplastic cells and to control the progression of the disease. Despite the advances obtained in this treatment modality, there are still cases of radioresistance, which can lead to an unfavorable prognosis. Therefore, it is crucial to conduct research focusing on the development of complementary therapies, aiming to favor the effectiveness of ionizing radiation. Plant-derived substances are excellent sources of discovery and development of new antineoplastic agents. Gallic acid (GA) is a potent antioxidant, derived from plants in the Brazilian cerrado, which can inhibit the development of neoplasms through various mechanisms such as inhibition of metastasis, suppression of angiogenesis, induction of apoptosis, inhibition of proliferation, migration and invasion. Based on the involvement of reactive oxygen species (ROS) in the pathogenesis of oral cancer, antioxidants have been the target of scientific research, investigating the use of these substances as ROS modulators in preventing oral cancer or, conversely, as inducers of the generation of ROS, to promote oxidative stress and death of OSCC cells. This work presents two aspects of study: the first aimed to review the literature on antineoplastic potential of antioxidant substances in oral squamous cell carcinoma. The second was to investigate the adjuvant action of GA on the therapeutic effect of ionizing radiation in OSCC cells. The systematic review of the first study involved the search for in vitro and clinical studies related to the proposed objective. The study was registered on the International Platform Prospero (CRD42018107206) and followed the search criteria of the PRISMA Platform for systematic reviews and meta-analyzes, using PubMed, Scopus, Web of Science and EBSCO databases, 260 publications were identified, with 32 articles eligible for full-text reading. The main antioxidant sources identified in this study with therapeutic potential in OSCC were Curcumin, Quercetin, Resveratrol, Licochalcones, α-mangostin, Shikonin, Pterostilbene, 2,4-bis (p-hydroxyphenyl) -2-butenal, β-lapachone and 3- iodine derivates, Selenium, Butein, Fisetin, Oridonin, Betulinic acid, Thymol, Verbacoside, Xanthorrhizol, and derivatives of Dihydrocaffeic acid amide. Several of these substances are polyphenols, terpenoids or flavonoids. Different plant extracts and dilutions of honey have also been shown to have antioxidant properties and exert antineoplastic effects, including methanol extract from Gracilaria tenuistipitata, methanol extract from Pergularia daemia, ethanol extract from Acacia catechu seed, alcohol extract from Salvia miltiorrhiza, extract from Areca nut, Duchesnea indica extract, Hibiscus sabdariffa extract and Tualang honey. All of these substances had biological effects on OSCC cells, controlling proliferation or leading to cell death. In the second part of this study, in vitro assays of proliferation, cell death, and levels of reactive oxygen species (ROS) were performed. Immortalized cells of CEB, SCC-9, and normal HaCaT keratinocytes, used as controls, were treated with GA at a concentration of 10 µg/ml, followed by exposure to 2, 4 and 6Gy of irradiation, in a linear accelerator. GA significantly reduced the number of viable cells at different doses of radiation and potentiated radio-induced cell death in OSCC cells, but not in HaCaT cells. In agreement with these findings, there was an increase in the intracellular accumulation of ROS in SCC-9 cells and a reduction in HaCaT. Thus, GA exerted a potential effect as an adjunct to therapeutic ionizing radiation in the behavioral control of OSCC cells, in addition to acting as a protector of normal keratinocytes. Further in vivo studies are needed to better understand the role of GA and other antioxidants as a promising therapeutic strategy against oral cancer.