RESUMEN
BACKGROUND: Melanoma is the most aggressive skin cancer, and BRAF (V600E) is the most frequent mutation that led to the development of BRAF inhibitors (BRAFi). However, patients treated with BRAFi usually present recidivism after 6-9 months. Curcumin is a turmeric substance, and it has been deeply investigated due to its anti-inflammatory and antitumoral effects. Still, the low bioavailability and biodisponibility encouraged the investigation of different analogs. DM-1 is a curcumin analog and has shown an antitumoral impact in previous studies. METHODS: Evaluated DM-1 stability and cytotoxic effects for BRAFi-sensitive and resistant melanomas, as well as the role in the metalloproteinases modulation. RESULTS: DM-1 showed growth inhibitory potential for melanoma cells, demonstrated by reduction of colony formation, migration and endothelial tube formation, and cell cycle arrest. Subtoxic doses were able to downregulate important Metalloproteinases (MMPs) related to invasiveness, such as MMP-1, -2 and -9. Negative modulations of TIMP-2 and MMP-14 reduced MMP-2 and -9 activity; however, the reverse effect is seen when increased TIMP-2 and MMP-14 resulted in raised MMP-2. CONCLUSION: These findings provide essential details into the functional role of DM-1 in melanomas, encouraging further studies in the development of combinatorial treatments for melanomas.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Melanoma/tratamiento farmacológico , Metaloproteasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Melanoma/metabolismo , Melanoma/patología , Metaloproteasas/metabolismo , Estructura Molecular , Proteínas Proto-Oncogénicas B-raf/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Background: Melanoma is the most aggressive skin cancer, and BRAF (V600E) is the most frequent mutation that led to the development of BRAF inhibitors (BRAFi). However, patients treated with BRAFi usually present recidivism after 6-9 months. Curcumin is a turmeric substance, and it has been deeply investigated due to its anti-inflammatory and antitumoral effects. Still, the low bioavailability and biodisponibility encouraged the investigation of different analogs. DM-1 is a curcumin analog and has shown an antitumoral impact in previous studies. Methods: Evaluated DM-1 stability and cytotoxic effects for BRAFi-sensitive and resistant melanomas, as well as the role in the metalloproteinases modulation. Results: DM-1 showed growth inhibitory potential for melanoma cells, demonstrated by reduction of colony formation, migration and endothelial tube formation, and cell cycle arrest. Subtoxic doses were able to downregulate important Metalloproteinases (MMPs) related to invasiveness, such as MMP-1, -2 and -9. Negative modulations of TIMP-2 and MMP-14 reduced MMP-2 and -9 activity; however, the reverse effect is seen when increased TIMP-2 and MMP-14 resulted in raised MMP-2. Conclusion: These findings provide essential details into the functional role of DM-1 in melanomas, encouraging further studies in the development of combinatorial treatments for melanomas.
RESUMEN
In recent years, several drugs have been approved for the treatment of patients with metastatic cutaneous melanoma, completely reshaping the landscape of this aggressive disease. Immune therapy with cytotoxic T-lymphocyte antigen 4 and programmed cell death-1 inhibitors yielded significant and durable responses, achieving long-term disease control in up to 40% of the patients. BRAF inhibitors (BRAFi), in combination with MEK inhibitors, also resulted in improved overall survival compared with single-agent BRAFi in patients with BRAFV600-mutated metastatic melanoma. The optimized sequencing and duration of treatment, however, is yet to be found. In this article, we thoroughly review current data and discuss how to best sequence the various treatment modalities available at present, based on four distinct clinical presentations commonly seen in clinic. In addition, we review treatment options beyond checkpoint inhibitors and targeted therapy, which may be required by patients failing such effective treatments.
RESUMEN
OBJECTIVE: This study is a characterization of the treatment patterns and outcomes of a Brazilian melanoma cohort collected of 1848 patients enrolled between 1996 and 2015. RESULTS: The superficial spreading subtype (35.1%) was the most prevalent, and the favoured anatomical location was the trunk (32.8%). The most common clinical stage was I (27.6%). The most frequent initial treatment was surgery (84.7%). Sentinel node biopsy was positive in 23.3% of cases. Chemotherapy was used to treat 298 patients (16.1%), immunotherapy for 67 (3.6%) and targeted therapy for 19 (1.0%). Distant recurrence was commonly observed (22.5%) and the mutation status of the BRAF gene was verified in 132 cases, with 42.4% positivity in this subset of patients. The melanoma specific actuarial 5-year survival for the cohort was 68.8%. There was a higher 5-year survival observed in metastatic melanoma patients who received immunotherapy and/or targeted therapy (34.2%) compared patients treated with just chemotherapy (20.0%). The survival analysis showed that sex, age, Breslow, clinical stage and distant recurrence were significant prognostic factors. This study provides a real-world description of how the introduction of new therapies such as immunotherapy and BRAF inhibitors is changing treatment strategies for melanoma in developing countries.