Abstract
Due to its aggressiveness and high mortality rate, oral cancer still represents a tough challenge for current cancer therapeutics. Similar to other carcinomas, cancerous invasion and metastasis are the most important prognostic factors and the main obstacles to therapy for human oral squamous cell carcinoma (OSCC). Fortunately, with the rise of the nanotechnical era and innovative nanomaterial fabrication, nanomaterials are widely used in biomedicine, cancer therapeutics, and chemoprevention. Recently, phytochemical substances have attracted increasing interest as adjuvants to conventional cancer therapy. The ginger phenolic compound zingerone, a multitarget pharmacological and bioactive phytochemical, possesses potent anti-inflammatory, antioxidant, and anticancer activities. In our previous study, we generated phytochemically derived zingerone nanoparticles (NPs), and documented their superior antitumorigenic effect on human hepatoma cells. In the present study, we further investigated the effects of zingerone NPs on inhibiting the invasiveness and metastasis of human OSCC cell lines. Zingerone NPs elicited significant cytotoxicity in three OSCC cell lines compared to zingerone. Moreover, the lower dose of zingerone NPs (25 µM) markedly inhibited colony formation and colony survival by at least five-fold compared to zingerone treatment. Additionally, zingerone NPs significantly attenuated cell motility and invasiveness. In terms of the signaling mechanism, we determined that the zingerone NP-mediated downregulation of Akt signaling played an important role in the inhibition of cell viability and cell motility. Zingerone NPs inhibited matrix metalloproteinase (MMP) activity, which was highly correlated with the attenuation of cell migration and cell invasion. By further detecting the roles of zingerone NPs in epithelial–mesenchymal transition (EMT), we observed that zingerone NPs substantially altered the levels of EMT-related markers by decreasing the levels of the mesenchymal markers, N-cadherin and vimentin, rather than the epithelial proteins, ZO-1 and E-cadherin, compared with zingerone. In conclusion, as novel and efficient phytochemically derived nanoparticles, zingerone NPs may serve as a potent adjuvant to protect against cell invasion and metastasis, which will provide a beneficial strategy for future applications in chemoprevention and conventional therapeutics in OSCC treatment.
Highlights
The major subtypes of head and neck squamous cell carcinomas (HNSCCs) are derived from the oral cavity and oropharynx
We further validated the effect of zingerone NPs on human oral squamous cell carcinoma (OSCC)
We found that zingerone NPs significantly attenuated MMP2 and MMP9 activity in these three OSCC cell lines compared to zingerone treatment (Figure 6A–C)
Summary
The major subtypes of head and neck squamous cell carcinomas (HNSCCs) are derived from the oral cavity and oropharynx. Several risk factors have been suggested to be responsible for the etiopathogenesis of oral squamous cell carcinoma (OSCC), including smoking or tobacco consumption, drinking alcohol, chewing areca nut or betel quid [3,4], and infection with human papillomavirus (HPV) [5] or pathogenic and commensal strains of bacteria [6], as well as other associated causes [7,8]. These risks are all involved in chronic inflammation and may lead to the development of oral carcinogenesis. Patients who suffer from oral cancer endure multiple negative psychosocial effects from individuals, families, and health care providers, and physical changes caused by adverse effects on the face, speech, voice, and swallowing, as well as financial impacts that all increase burdens and affect patients’ quality of life [10]
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