Abstract
Isoalantolactone is a sesquiterpene lactone compound isolated from the roots of Inula helenium L. Previous studies have demonstrated that isoalantolactone possesses antifungal, anti-bacterial, anti-helminthic and anti-proliferative properties in a variety of cells, but there are no studies concerning its effects on head and neck squamous cell carcinoma (HNSCC). In the present study, an MTT assay demonstrated that isoalantolactone has anti-proliferative activity against the HNSCC cell line (UM-SCC-10A). Immunostaining identified that this compound induced UM-SCC-10A cell apoptosis but not necrosis. To explain the molecular mechanisms underlying its effects, flow cytometry and western blot analysis showed that the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and p21, and down-regulation of cyclin D. Furthermore, our results revealed that induction of apoptosis through a mitochondrial pathway led to up-regulation of pro-apoptotic protein expression (Bax), down-regulation of anti-apoptotic protein expression (Bcl-2), mitochondrial release of cytochrome c (Cyto c), reduction of mitochondrial membrane potential (MMP) and activation of caspase-3 (Casp-3). Involvement of the caspase apoptosis pathway was confirmed using caspase inhibitor Z-VAD-FMK pretreatment. Together, our findings suggest that isoalantolactone induced caspase-dependent apoptosis via a mitochondrial pathway and was associated with cell cycle arrest in the G1 phase in UM-SCC-10A cells. Therefore, isoalantolactone may become a potential drug for treating HNSCC.
Highlights
The sixth most common form of cancer worldwide is head and neck cancer [1], of which 90% of cases are head and neck squamous cell carcinoma (HNSCCs), which refers to squamous cell carcinoma (SCC) arising from the mucosal surfaces of the oral cavity, oropharynx, larynx or hypopharynx
The results indicate that isoalantolactone induced caspase-dependent apoptosis via a mitochondrial pathway and was associated with cell cycle arrest in the G1 phase in UM-SCC-10A cells
Our results showed that the membrane potential (MMP) of the UM-SCC-10A cells decreased significantly after treatment with isoalantolactone in a dosedependent manner, suggesting that isoalantolactone induced cell apoptosis through the intrinsic pathway (Figure 5)
Summary
The sixth most common form of cancer worldwide is head and neck cancer [1], of which 90% of cases are head and neck squamous cell carcinoma (HNSCCs), which refers to squamous cell carcinoma (SCC) arising from the mucosal surfaces of the oral cavity, oropharynx, larynx or hypopharynx. HNSCC is the eighth most common cause of mortality due to cancer worldwide and is known to be difficult to treat; it has only a 50% fiveyear survival rate [2]. During the past few decades, aggressive and combined treatment regimens have been used, including chemoradiation, radical surgery, and neoadjuvant chemotherapy, depending on the site, size and stage of the lesions. Surgery is usually performed for early-stage disease, and radiotherapy always has a variety of severe adverse affects. Developing novel chemotherapeutic agents with less toxicity and understanding their molecular mechanisms are necessary for improving HNSCC outcomes
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