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ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.

ABSTRACT: Oxidative stress is a barrier of migration and metastasis for malignant melanoma cells. Consequently, reducing oxidative stress with the antioxidant N-acetylcysteine (NAC) stimulates melanoma cell migration in vitro and metastasis in vivo. However, it is not yet known whether the NAC effect is shared with other antioxidants. Here, we screened 104 redox-active compounds and identify 27 that increase migration of human malignant melanoma cells in two doses. Validation experiments in four cell lines and four drug doses resulted in a list of 18 compounds which were ranked based on their ability to increase migration and reduce ROS levels; vitamin C (VitC) ranked as number one, followed by the vitamin E analogue Trolox and several carotenoids and Vitamin A-related compounds. Four diet-relevant compounds from this list-VitC, β-carotene, retinyl palmitate, and canthaxanthin-were selected and found to accelerate metastasis in mice with BRAF^V600E-driven malignant melanoma. Genomics analyses revealed that the transcription factor BACH1 is activated following antioxidant administration and knockout of Bach1 in mouse melanoma cells reduced lymph node and liver metastasis in xenograft mouse models. We conclude that a broad range of antioxidants accelerate melanoma migration and metastasis and that BACH1 is functionally linked to melanoma metastasis in vivo.

SUBMITTER: Kashif M

PROVIDER: S-EPMC9945759 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.

Kashif Muhammad M Yao Haidong H Schmidt Sarah S Chen Xue X Truong Michelle M Tüksammel Elin E Liu Yiran Y Bergo Martin O MO

Redox biology 20230202

Oxidative stress is a barrier of migration and metastasis for malignant melanoma cells. Consequently, reducing oxidative stress with the antioxidant N-acetylcysteine (NAC) stimulates melanoma cell migration in vitro and metastasis in vivo. However, it is not yet known whether the NAC effect is shared with other antioxidants. Here, we screened 104 redox-active compounds and identify 27 that increase migration of human malignant melanoma cells in two doses. Validation experiments in four cell line ...[more]

PMID: 36774779

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Project description:The incidence of malignant melanoma is increasing worldwide and is one of the major causes of skin cancer deaths in the United States. Although melanoma has the potential to metastasize to any organ, the incidence of bone metastasis is low (~25%) compared to liver or lung metastasis. However, when a bone is involved, metastasis occurs to the axial skeleton in most cases (80%-90%), and involvement of the appendicular skeleton is relatively rare. We here describe the case of a patient who presented with a pathological fracture due to extra-axial skeletal metastasis of a widespread malignant melanoma. A 45-year-old female with an unremarkable past medical history presented to the ED with acute left hip pain. X-ray demonstrated left intertrochanteric femur fracture with an abnormal, suspicious lesion at the fracture site. Detailed physical examination revealed various skin nodules on the anterior chest wall, right upper back, and left cheek. CT of the chest/abdomen/pelvis (CT C/A/P) showed multiple lytic bone lesions and metastatic lesions in lungs, soft tissue, and mediastinal lymph nodes. She underwent surgical stabilization of the fracture, and a biopsy of the bone lesion revealed metastatic malignant melanoma with BRAF V600E mutation. She was started on localized radiotherapy followed by targeted therapy (dabrafenib and trametinib) and denosumab for her stage IV (cTX, cN2, cM1b(1)) (American Joint Committee on Cancer [AJCC] cancer staging 8th edition) disease. Despite treatment, her disease progressed as evidenced by the presence of new metastatic foci on a positron emission tomography-computed tomography (PET-CT) scan performed at a three-month follow-up. Her clinical course was complicated by hemoperitoneum due to bleeding from metastatic liver lesions and respiratory failure requiring a prolonged stay in the ICU before she was deceased. In most cases, malignant melanoma presents with skin lesions at an early stage. Very few patients (4%) have metastatic disease at presentation. Although metastasis to bone is known to occur in advanced disease, involvement of the extra-axial skeleton is relatively rare. Malignant melanoma, initially presenting as pathological fracture of the appendicular skeleton, is not commonly encountered. Our case emphasizes the aggressive nature of malignant melanoma with an aim to raise physicians' awareness of this uncommon presentation. A brief review of the literature exploring prognosis and currently available treatment options is discussed.

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ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.

Publications

ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.

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