Artepillin C as a targeting survivin molecule in oral squamous cell carcinoma cells in vitro: A preliminary study

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Head and neck cancer is the ninth most common cancer in the United States, accounting for 3.3% of all cancers.1 It was estimated that approximately 45 780 individuals would be diagnosed with and 8650 deaths would result from head and neck cancer in 2015 in the United States.2 Oral squamous cell carcinoma (OSCC) is the most common oral and pharyngeal cancer. Despite aggressive management, such as surgery, radiation, and chemotherapy, prognosis for patients with advanced stage OSCC remains poor.
Cells are continuously exposed to stress, including oncogenic stress, genomic instability, and cellular hypoxia. Such stimuli would normally trigger the intrinsic pathway of apoptosis in normal cells. However, cancer cells can often evade this response by disabling apoptotic pathways. There are many mechanisms by which cancer cells can reduce or acquire resistance to apoptosis.3 In general, cancer cells can interfere transcriptionally and translationally with the apoptotic pathway by inducing the expression of anti‐apoptotic proteins and/or by suppressing the expression of pro‐apoptotic proteins.4 In addition, approximately 50% of OSCCs have a dysfunctional p53, resulting in the loss of an important checkpoint control mechanism. Thus, OSCC cells are resistant to undergoing apoptosis, and this may play a role, at least in part, in chemoresistance of cancer cells. Recently, the targeted elimination of cancer cells by inducing apoptosis has emerged as a valued strategy to combat malignancies.
One of the most promising approaches to eliminate cancer cells is to target molecules that are overexpressed by cancer cells and involved in their growth, proliferation, and survival. Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is highly expressed in most cancer cells, but not in terminally differentiated normal cells.5 It has dual roles as an anti‐apoptotic factor and a mitotic inducer and is one of the key molecules for embryonic and fetal development.6 The anti‐apoptotic activity of survivin is mediated mainly in a caspase‐dependent manner.7 Therefore, antagonizing survivin is a promising therapeutic approach to trigger apoptosis in cancer cells. A recent study has shown that silencing the survivin gene in OSCC cells results in a higher apoptotic rate compared to treatment with 5‐fluorouracil (5‐FU).8 It has also been reported that deletion of survivin results in cell cycle arrest at the S phase or G2/M phase, followed by apoptosis, in HepG2 hepatocellular carcinoma cells.9
Artepillin C (3,5‐diprenyl‐4‐hydroxycinnamic acid) is the major biologically active phenolic component found in Brazilian propolis and has various physiological and biochemical functions.10 Artepillin C is a ligand for peroxisome proliferator‐activated receptor (PPAR)‐γ.15 Artepillin C inhibits tumor growth both in vivo and in vitro by inducing apoptosis.11 It also sensitizes TRAIL‐resistant prostate cancer cells to tumor necrosis factor‐related apoptosis inducing ligand (TRAIL)‐mediated apoptosis.16 However, little is known about its effect on OSCC cells. In addition, whether or not artepillin C modulates survivin expression is not known. This study aimed to investigate the cytotoxicity and antisurvivin activity of artepillin C in OSCC cells as a potential novel therapeutic agent.
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