Abstract
Melanoma is extremely resistant to chemotherapy and the death rate is increasing hastily worldwide. Extracellular matrix promotes the migration and invasion of tumor cells through the production of matrix metalloproteinase (MMP)-2 and -9. Evidence has shown that natural dietary antioxidants are capable of inhibiting cancer cell growth. Our recent studies showed that hinokitiol, a natural bioactive compound, inhibited vascular smooth muscle cell proliferation and platelets aggregation. The present study is to investigate the anticancer efficacy of hinokitiol against B16-F10 melanoma cells via modulating tumor invasion factors MMPs, antioxidant enzymes in vitro. An in vivo mice model of histological investigation was performed to study the patterns of elastic and collagen fibers. Hinokitiol inhibited the expression and activity of MMPs-2 and -9 in B16-F10 melanoma cells, as measured by western blotting and gelatin zymography, respectively. An observed increase in protein expression of MMPs 2/9 in melanoma cells was significantly inhibited by hinokitiol. Notably, hinokitiol (1–5 μM) increased the activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) from the reduction in melanoma cells. Also, hinokitiol (2–10 µM) concentration dependently reduced in vitro Fenton reaction induced hydroxyl radical (OH·) formation. An in vivo study showed that hinokitiol treatment increased elastic fibers (EF), collagens dispersion, and improved alveolar alterations in the lungs of B16/F10 injected mice. Overall, our findings propose that hinokitiol may be a potent anticancer candidate through down regulation of MMPs 9/2, reduction of OH· production and enhancement of antioxidant enzymes SOD and CAT.
Highlights
Metastatic melanoma is one of the utmost fatal and ambiguous cancers responsible for 4% of skin cancers and 75% of skin cancer-related deaths [1]
Among other matrix metalloproteinase (MMP), MMPs-9 and -2 are known to play an important role in cancer cell invasion and metastasis, we examined whether hinokitiol could inhibit the expression of MMPs-9 and -2 in B16-F10 cells by using Western blot analysis
The results showed an apparent increase in expression levels of MMPs-9 and -2 in untreated B16-F10 melanoma cells
Summary
Metastatic melanoma is one of the utmost fatal and ambiguous cancers responsible for 4% of skin cancers and 75% of skin cancer-related deaths [1]. It can be controlled by multi-step processes such as tumor-induced angiogenesis, tumor invasion, and establishment of metastatic foci at the secondary site involving various molecules [2]. MMP-2 and MMP-9 are considered to be prognostic factors in many solid tumors, and found to promote invasion and metastasis of malignant tumors [4]. Elevated levels of MMP-2 and MMP-9 are often correlated with malignancies of liver, brain, breast, prostate, cervical, ovarian, and other cancers
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