RESUMO
Radiotherapy is a well-established cancer treatment; it is estimated that approximately 52% of oncology patients will require this treatment modality at least once. However, some tumors, such as triple-negative breast cancer (TNBC), may present as radioresistant and thus require high doses of ionizing radiation and a prolonged period of treatment, which may result in more severe side effects. Moreover, such tumors show a high incidence of metastases and decreased survival expectancy of the patient. Thus, new strategies for radiosensitizing TNBC are urgently needed. Red light therapy, photobiomodulation, has been used in clinical practice to mitigate the adverse side effects usually associated with radiotherapy. However, no studies have explored its use as a radiosensitizer of TNBC. Here, we used TNBC-bearing mice as a radioresistant cancer model. Red light treatment was applied in three different protocols before a high dose of radiation (60 Gy split in 4 fractions) was administered. We evaluated tumor growth, mouse clinical signs, total blood cell counts, lung metastasis, survival, and levels of glutathione in the blood. Our data showed that the highest laser dose in combination with radiation arrested tumor progression, likely due to inhibition of GSH synthesis. In addition, red light treatment before each fraction of radiation, regardless of the light dose, improved the health status of the animals, prevented anemia, reduced metastases, and improved survival. Collectively, these results indicate that red light treatment in combination with radiation could prove useful in the treatment of TNBC.
Assuntos
Radiossensibilizantes , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Modelos Animais de Doenças , Linhagem Celular Tumoral , Radiossensibilizantes/farmacologia , LuzRESUMO
PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, accounting for 20% of cases. Due to the lack of a molecular target, limited options are available for TNBC treatment. Radiation therapy (RT) is a treatment modality for the management of TNBC following surgery; however, it has a detrimental effect on surrounding healthy tissues/cells at a higher rate. METHODS: We examined the effect of RT in combination with chrysin as a possible radiosensitizing agent in an MDA-MB-231 cell line as a model of a TNBC. The growth inhibitory effects of chrysin were examined using an MTT assay. Flow cytometry was performed to evaluate apoptosis and expression of hypoxia-induced factor-1α (HIF-1α). The protein expression of p-STAT3/STAT3 and Cyclin D1 was examined using western blotting. Real-time PCR determined apoptotic-related genes (Bax, BCL2, p53). RESULTS: Treatment of MDA-MB-231 cells with chrysin in combination with RT caused synergistic antitumor effects, with an optimum combination index (CI) of 0.495. Our results indicated that chrysin synergistically potentiated RT-induced apoptosis in MDA-MB-231 compared with monotherapies (chrysin and/or RT alone). Expression of HIF-1α was decreased in the cells exposed to combinational therapy. The apoptotic effect of combinational therapy was correlated with increased Bax (pro-apoptotic gene) and p53 levels along with reduced expression of Bcl-2 (anti-apoptotic gene). Increased apoptosis was associated with reduced expression of Cyclin D1, p-STAT3. CONCLUSION: These findings highlight the potential effect of chrysin as a radiosensitizer, indicating the synergistic anti-cancer effect of chrysin and RT in TNBC. Further investigation is warranted in this regard.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/genética , Ciclina D1/metabolismo , Linhagem Celular Tumoral , Proteína Supressora de Tumor p53 , Proteína X Associada a bcl-2/metabolismo , Proliferação de Células , ApoptoseRESUMO
PURPOSE: To explore the roles and underlying mechanisms of miR-1290 in determining the sensitivity of triple-negative breast cancer (TNBC) to radiation therapy. METHODS: ELISA was performed to detect the levels of IL-18 and IL-1ß in radiosensitive cells and serum samples. The level of miR-1290 in radiosensitive cells and tissues was assessed by qRT-PCR assay. A luciferase reporter assay was performed to confirm NLRP3 as the target of miR-1290. Functionally, the roles of miR-1290 in TNBC radioresistance were analyzed by transfection of either miR-1290 mimic or miR-1290 inhibitor. Moreover, the involvement of the miR-1290/NLRP3 axis in TNBC radioresistance was analyzed by experiments with a miR-1290 mimic and NLRP3 overexpression. MTT and colony formation assays were used to detect radiation-induced cell viability and proliferation. qRT-PCR and western blot assays were used to detect pyroptosis markers (NLRP3, ACS and caspase-1). RESULTS: The results showed that radioresistance in TNBC cells was associated with a reduction in pyroptosis. miR-1290 expression was increased in radioresistant cells, and it had higher expression levels in the radioresistant tumor tissues of TNBC patients compared to the radiosensitive samples. The miR-1290 mimic suppressed radiation-induced pyroptosis and reduced the radiosensitivity of TNBC cells. Moreover, we found that NLRP3 was a potential target of miR-1290. Overexpression of NLRP3 partly reversed the effects of miR-1290 on pyroptosis and radioresistance. The mouse models showed that miR-1290 suppressed tumor size, tumor weight and pyroptosis. CONCLUSIONS: miR-1290/NLRP3-mediated pyroptosis may play an important role in determining radioresistance in TNBC and serve as a novel therapeutic option.
Assuntos
MicroRNAs , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tolerância a Radiação/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/radioterapiaRESUMO
This work investigated the effect of photobiomodulation therapy (PBM) combined with radiotherapy (RT) on triple-negative breast cancer (TNBC)-bearing mice. Female BALB/c mice received 4 T1 cells into a mammary fat pad. Local RT was performed with a total dose of 60 Gy divided into 4 consecutive sessions of 15 Gy. For PBM, a red laser was used in three different protocols: i-) single exposure delivering 150 J.cm-2 (24 h after the last RT session), and ii-) radiant exposure of 150 J.cm-2 or iii-) fractionated radiant exposure of 37.5 J.cm-2 (after each RT session). Tumor volume, complete blood cell count, clinical condition, metastasis, and survival of animals were monitored during 3 weeks post-RT. Our results demonstrated that regardless of the protocol, PBM arrested the tumor growth, improved the clinical condition, and prevented hemolytic anemia. Besides, although PBM groups have exhibited a high neutrophil:lymphocyte ratio (NLR), they decreased the number of lung metastases and enhanced mouse survival. Worthy of note, PBM should be used along with the RT sessions in higher radiant exposures, since PBM at 150 J.cm-2 per session significantly extended the survival rate. Together, these data suggest PBM could be a potential ally to RT to fight TNBC.
Assuntos
Terapia com Luz de Baixa Intensidade/métodos , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Feminino , Xenoenxertos , Humanos , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Resumen El cáncer de mama (CM) es la principal causa de muerte por cáncer en mujeres chilenas. Es una enfermedad heterogénea, en la cual se han identificado cuatro subtipos básicos, determinados según características clínicas, histológicas y moleculares, los que se relacionan a estrategias terapéuticas. El CM triple negativo (CMTN) se caracteriza por su agresividad, recaída temprana y mayor tendencia a presentarse en etapas avanzadas. Frecuentemente afecta a mujeres jóvenes o con antecedentes familiares de CM u ovario. La única terapia sistémica aprobada para el CMTN es la quimioterapia; sin embargo, recientemente terapias moleculares con inhibidores de puntos de control inmune e inhibidores de la poli-adenosina difosfato ribosa polimerasa, han mostrado eficacia en pacientes seleccionados, y se han agregado al arsenal terapéutico para CMTN. Dada la aparición de estas nuevas estrategias, parece relevante entender la heterogeneidad de esta enfermedad, los mecanismos de acción de las nuevas terapias, resultados clínicos y criterios de selección de pacientes para terapias moleculares. Presentamos una revisión de la terapia sistémica actual del CMTN.
Breast cancer is the leading cause of cancer death in Chilean women and worldwide. It is a heterogeneous disease and four different subtypes have been identified based on clinical, histological and molecular features, which correlate with different treatment tumor sensitivity. Triple negative breast cancer is characterized by its aggressiveness, early relapse, and a greater tendency to present in advanced stages. It frequently affects young women, with cancer family history, especially breast or ovarian cancer. The approved systemic therapy for triple negative breast cancer is chemotherapy; however, recently, targeted therapies with checkpoint inhibitors and polyadenosine diphosphate ribose polymerase inhibitors have been shown to be effective in selected patients and have been added to the therapeutic arsenal for triple negative breast cancer. Given the appearance of these new strategies, it seems relevant to understand the heterogeneity of this disease, the mechanisms of action behind new therapies, clinical results, and the criteria to select patients for molecular therapies. We present a review of the current systemic therapy of this breast cancer subtype.