Efeito do tratamento com melatonina associado ao paclitaxel em células de carcinoma ovariano
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Data
2022-02-17
Autores
Gaiotte, Leticia Barbosa
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O câncer de ovário (CO) é uma doença ginecológica com altas taxas de mortalidade entre as mulheres. Embora a maioria dos pacientes responda à quimioterapia convencional [por exemplo, paclitaxel (PTX)], muitas mulheres se tornam resistentes e a doença progride. A melatonina exerce funções antioxidantes, antitumorais e imunomoduladoras em uma variedade de tumores sólidos. Portanto, este estudo investigou os efeitos do PTX combinado com melatonina na via inflamatória mediada pelo receptor toll-like (TLR), sinalização celular e sobrevivência de células de carcinoma de ovário humano SKOV-3. O ensaio de citometria de fluxo mostrou que a melatonina associada ao PTX promoveu um aumento significativo nas taxas de apoptose/necrose. A migração celular foi atenuada apenas pela melatonina e, após sua associação com PTX, o número de células migradas e invasivas reduziu significativamente. Embora o tratamento combinado de PTX e melatonina não tenha sido capaz de reduzir TLR2, os níveis de TLR4, MyD88, TRIF e PD-L1 foram reduzidos após a combinação de terapia e até melatonina sozinha. Além disso, a terapia combinada reduziu significativamente os níveis de NF-kB p65, p-PI3K, p-AKT, p38, ERK 1/2, JNK, CREB, p70s6K e STAT 5. Concluímos que o tratamento combinado foi eficaz na redução Viabilidade e capacidade invasiva das células OC enquanto aumenta as taxas de apoptose e necrose. Além disso, a combinação atenuou as moléculas a jusante da via inflamatória mediada por TLR4 e proteínas relacionadas à sinalização celular em células SKOV-3, mostrando-se, assim, capaz de promover alterações na resposta celular e em seu potencial maligno. A melatonina pode melhorar a quimiossensibilidade do PTX, servindo como uma terapia adjuvante eficaz contra OC.
Ovarian cancer (OC) is a gynecological disease with high mortality rates among women. Although most patients respond to the conventional chemotherapy [e.g., paclitaxel (PTX)], many women become resistant and the disease progresses. Melatonin exerts antioxidants, antitumor, and immunomodulatory functions in a variety of solid tumors. Therefore, this study investigated the effects of PTX combined with melatonin on the toll-like receptor (TLR) mediated inflammatory pathway, cell signaling, and survival of SKOV-3 human ovarian carcinoma cells. The flow cytometry assay showed that melatonin associated with PTX promoted a significant increase in apoptosis/necrosis rates. The cell migration was attenuated by melatonin alone, and after its association with PTX, the number of migrated and invasive cells reduced significantly. Although the combined treatment of PTX and melatonin was unable to reduce TLR2, the levels of TLR4, MyD88, TRIF, and PD-L1 were reduced following therapy combination and even melatonin alone. Furthermore, the combination therapy significantly reduced the levels of NF-kB p65, p-PI3K, p-AKT, p38, ERK 1/2, JNK, CREB, p70s6K, and STAT 5. We concluded that the combined treatment was effective in reducing OC cell viability and invasive capacity while increasing apoptosis and necrosis rates. Moreover, the combination attenuated the downstream molecules of the TLR4-mediated inflammatory pathway and cell signaling-related proteins in SKOV-3 cells, thus proving to be capable of promoting changes in the cellular response and in its malignant potential. Melatonin may improve the chemosensitivity of PTX, serving as an effective adjuvant therapy against OC.
Ovarian cancer (OC) is a gynecological disease with high mortality rates among women. Although most patients respond to the conventional chemotherapy [e.g., paclitaxel (PTX)], many women become resistant and the disease progresses. Melatonin exerts antioxidants, antitumor, and immunomodulatory functions in a variety of solid tumors. Therefore, this study investigated the effects of PTX combined with melatonin on the toll-like receptor (TLR) mediated inflammatory pathway, cell signaling, and survival of SKOV-3 human ovarian carcinoma cells. The flow cytometry assay showed that melatonin associated with PTX promoted a significant increase in apoptosis/necrosis rates. The cell migration was attenuated by melatonin alone, and after its association with PTX, the number of migrated and invasive cells reduced significantly. Although the combined treatment of PTX and melatonin was unable to reduce TLR2, the levels of TLR4, MyD88, TRIF, and PD-L1 were reduced following therapy combination and even melatonin alone. Furthermore, the combination therapy significantly reduced the levels of NF-kB p65, p-PI3K, p-AKT, p38, ERK 1/2, JNK, CREB, p70s6K, and STAT 5. We concluded that the combined treatment was effective in reducing OC cell viability and invasive capacity while increasing apoptosis and necrosis rates. Moreover, the combination attenuated the downstream molecules of the TLR4-mediated inflammatory pathway and cell signaling-related proteins in SKOV-3 cells, thus proving to be capable of promoting changes in the cellular response and in its malignant potential. Melatonin may improve the chemosensitivity of PTX, serving as an effective adjuvant therapy against OC.
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Palavras-chave
Câncer de ovário, Melatonina, Paclitaxel, Receptor toll-like, PD-L1, Sinalização celular, Ovarian cancer, Melatonin, SKOV-3 cells