Abstract
Oral cancer (OC) has been attracted research attention in recent years as result of its high morbidity and mortality. Costunolide (CTD) possesses potential anticancer and bioactive abilities that have been confirmed in several types of cancers. However, its effects on oral cancer remain unclear. This study investigated the potential anticancer ability and underlying mechanisms of CTD in OC in vivo and in vitro. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of CTD on OC cells; assessments for migration and invasion of OC cells were conducted by transwell; Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. The results revealed that CTD suppressed the proliferation, migration and invasion of oral cancer cells effectively and induced cell cycle arrest and apoptosis; regarding the mechanism, CTD bound to AKT directly by binding assay and repressed AKT activities through kinase assay, which thereby downregulating the downstream of AKT. Furthermore, CTD remarkably promotes the generation of reactive oxygen species by flow cytometry assay, leading to cell apoptosis. Notably, CTD strongly suppresses cell-derived xenograft OC tumor growth in an in vivo mouse model. In conclusion, our results suggested that costunolide might prevent progression of OC and promise to be a novel AKT inhibitor.
Highlights
More than 90% of oral cancer cases are of the oral squamous cell carcinoma (OSCC) type, which have been associated with alcohol consumption, human papillomavirus (HPV), smoking and betel quid chewing, and are the potential risk factors in the development of OSCC [2,3,4]
We analyzed the caspase activity by western blotting and observed that the expressions of cleaved caspase-3 and caspase-9 were promoted and the expression of AIF (Apoptosis Inducing Factor) was increased related to ER stress (Figure 7G). These findings suggested that CTD triggered apoptosis in association with excess Reactive oxygen species (ROS) generation
Considering the hyperactivation of the PI3K/AKT/mTOR pathway in Head and Neck squamous cell carcinoma (HNSCC), targeting this pathway has become a significant approach for oral cancer treatment, where are responsible for in both in therapy resistance and cell proliferation to some extent [11,12,34]
Summary
Oral cancer is a type of head and neck squamous carcinoma (HNSC) and the sixth most common cancer worldwide with a high mortality rate [1]. More than 90% of oral cancer cases are of the oral squamous cell carcinoma (OSCC) type, which have been associated with alcohol consumption, human papillomavirus (HPV), smoking and betel quid chewing, and are the potential risk factors in the development of OSCC [2,3,4]. Used therapies for oral cancer include surgery, radiation therapy and chemotherapy alone or their combination, such as anlotinib [6], cetuximab [7] and PD-1/PD-L1 [8]. Cisplatin and 5-fluorouracil are commonly used in combination, and cisplatin is effective when used alone as well [9], the survival rate remains poor
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