Ocoxin Increases the Antitumor Effect of BRAF Inhibition and Reduces Cancer Associated Fibroblast-Mediated Chemoresistance and Protumoral Activity in Metastatic Melanoma

Abstract

Whereas the prevalence of several cancer types is decreasing, skin malignancies are growing more common every year. Malignant melanoma is the most aggressive form of skin cancer with high metastatic capacity. In most cases, malignant melanoma shows acquired therapy resistance. We evaluated the ability of Ocoxin, a natural compound-based antioxidant and anti-inflammatory nutritional complement, to exert an antitumor effect in melanoma. To do so, the cytotoxicity of Ocoxin in a panel of BRAF-mutated murine and human melanoma cell lines was tested alone and in combination with BRAF inhibitor Vemurafenib. Our results revealed a potent cytotoxic effect of Ocoxin against melanoma cells and a synergic effect when combined with Vemurafenib, reducing viability and increasing apoptosis. Besides, Ocoxin interferes with the cell cycle, impairs the inherent and fibroblast-mediated melanoma cell migration, and reduces resistance to BRAF inhibition. Proteomic analysis revealed reduced tumor secretion of inflammatory factors Galectin-1, Osteopontin, CCL5, and CCL9 upon treatment with Ocoxin. Moreover, RNASeq showed that Ocoxin downregulated the cell cycle and proliferation-related genes. In vivo, Ocoxin reduced the number of lung metastasis of YUMM-1.7 melanoma cells. Therefore, Ocoxin arises as a good candidate for clinical trials analyzing the beneficial effects in patients suffering from this cutaneous malignancy.

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives

“…In addition, cancer-associated fibroblasts mediate Gal-1 regulation of cancer cell motility through macrovesicle release, and knockdown of Gal-1 prevents cancer-associated fibroblast-mediated prostate and pancreatic cancer migration [ 136 ]. This finding is in agreement with previously described cancer-associated fibroblasts expressing Gal-1 to promote melanoma cell migration [ 154 ]. The possible mechanism might be due to Gal-1’s interaction with integrin-β1 on fibroblasts to activate Gli1 expression, resulting in increased metastasis of gastric cancer [ 86 ].…”

Immunonutrition hope? Oral nutritional supplement on cancer treatment

“…Breast cancer, acute myeloid leukaemia (AML), colorectal cancer (CRC) metastasis to the liver, HCC, small‐cell lung cancer (SCLC), pancreatic adenocarcinoma, glioblastoma (GBM) and melanoma were the types of cancers described. All of them were performed in Spain 7,12‐15,21‐25 …”

“…All of them were performed in Spain. 7,[12][13][14][15][21][22][23][24][25] Table S1 describes in detail the characteristics of basic and human included studies.…”

“…13 Also, Oncoxin ® has recently been shown to interfere in the tumour microenvironment by reducing the fibroblast-mediated tumour progression, overcoming resistance against targeted therapy with the BRAF inhibitor and impairing fibroblast-mediated tumour cell migration in melanoma cell lines in vitro and in vivo. 25 Such potentials need to be confirmed in clinical trials.…”

“…We found a total of 38 studies with search strategies and three with other sources. After exclusions, we finally included 16 studies in the qualitative analysis 7,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] (Figure 1).…”