Zingerone suppresses angiogenesisviainhibition of matrix metalloproteinases during tumor development

Abstract

Angiogenesis is an essential step for tumor survival and progression, and the inhibition of angiogenesis is a good strategy for tumor therapeutics. In this study, we investigated the therapeutic effect of zingerone in a mouse tumor model. Zingerone suppressed tumor progression and tumor angiogenesis. Moreover, we found that zingerone inhibited the angiogenic activities of endothelial cells by both direct and indirect means. A mechanistic study showed that the activities of MMP-2 and MMP-9 in tumor cells were decreased by treatment with zingerone. Interestingly, zingerone-mediated inhibition of MMP-2 and MMP-9 was involved in the JNK pathway. In conclusion, zingerone showed strong anti-angiogenic activity via the inhibition of MMP-2 and MMP-9 during tumor progression, suggesting that zingerone may be a potential therapeutic drug for human cancers.

Zingerone Suppresses Tumor Development through Decreasing Cyclin D1 Expression and Inducing Mitotic Arrest

“…Approximately 50% of Food and Drug Administration (FDA)-approved drugs are either natural products, such as phytochemicals, or their derivatives [ 39 ]. Our group demonstrated the anti-angiogenic properties of zingerone as a natural compound in tumor models in vitro and in vivo [ 14 ]. Zingerone is not only extremely safe in vivo, but also functions through a unique mechanism of action leading to the inhibition of matrix metalloproteinases (MMP)-2 and MMP-9, which are involved in the c-Jun N-terminal kinase (JNK) pathway in tumorigenesis [ 14 ].…”

“…Our group demonstrated the anti-angiogenic properties of zingerone as a natural compound in tumor models in vitro and in vivo [ 14 ]. Zingerone is not only extremely safe in vivo, but also functions through a unique mechanism of action leading to the inhibition of matrix metalloproteinases (MMP)-2 and MMP-9, which are involved in the c-Jun N-terminal kinase (JNK) pathway in tumorigenesis [ 14 ]. Deregulated cell-cycle regulators, including mitosis regulators, are implicated in tumor development and poor survival from cancer treatments.…”

“…Zingerone has a methoxy group attached to a benzene ring [ 12 ]. Zingerone showed anti-cancer effects in rat colon cancer [ 13 ] and anti-angiogenic activity during tumorigenesis [ 14 ]. However, although phenolic compounds are suggested to exert chemopreventive effects [ 7 ], the anti-cancer effects of zingerone are yet to be thoroughly studied.…”

In vitro assays and techniques utilized in anticancer drug discovery

“…Different assay approaches based on immunochemical and enzyme activities have been introduced by several manufacturers to assess MMP activity at cellular level. The activity of MMP‐2 and MMP‐9 was measured in a study conducted by Bae, Choi, Kim, Park, and Jeong () to confirm suppression of angiogenesis by zingerone, a well‐known compound found in Zingiber officinale . The effects of naringin (a flavonoid) on the expression of MMP‐2, MMP‐9 enzymes have been measured in a study carried out by Aroui et al ( ) .…”

“…Different assay approaches based on immunochemical and enzyme activities have been introduced by several manufacturers to assess MMP activity at cellular level. The activity of MMP-2 and MMP-9 was measured in a study conducted by Bae, Choi, Kim, Park, and Jeong (2016)…”