口腔鱗狀細胞癌（OSCC）在全世界內是一種具有高發病率和死亡率的癌症。目前用於OSCC的化療藥物是順鉑(Cisplatin)，5-氟尿嘧啶（5-fluorouracil；5-FU），博萊黴素(Bleomycin)，絲裂黴素-C (Mitomycin-c)，甲氨蝶呤（Methotrexate；MTX）和奧沙利鉑（Oxaliplatin；FOLFOX4），替加氟/尿嘧啶（Tegafur/uracil；UFUR）。儘管科學研究迅速，醫學技術成果先進，但過去10年來口腔鱗癌的預後仍然很差。當前新藥的研究重點是尋找一種對於抗藥性癌細胞具低副作用，高療效的藥物。植化素為植物含有的天然化學物質，由於植化素存在於植物本身，因此人類飲食中常見的水果、蔬菜，甚至是中藥草皆含有豐富的植化素。本實驗研究重點為熊果酸與薑黃素兩種存在於人們普遍飲食當中的植物成分。隨著近年天然藥物研究的迅速發展，發現熊果酸與薑黃素具有抗氧化、抗發炎、抗菌和抗癌等廣泛的藥理作用。因此本實驗分為兩部分：(1)熊果酸對於人類順鉑耐性口腔癌細胞的藥理探討(2)薑黃素協同西妥昔單抗(Cetuximab)於抗順鉑口腔癌細胞的藥理探討。我們實驗室先前建立了人類順鉑耐性的口腔癌細胞株(CAR細胞)，首先以熊果酸作用於CAR細胞，我們的結果發現熊果酸能夠透過降低AKT、磷酸化的BAD、Bcl-2和Bcl-xL的蛋白表現量，使ROS增加與粒線體膜電位（ΔΨm）下降，最後觸發caspase-3,9表現量上升，引起CAR細胞走向凋亡路徑。另外利用薑黃素與西妥昔單抗一起處理CAR細胞，發現薑黃素與西妥昔單抗能夠具有加乘性的抑制CAR細胞的生長，並透過抑制EGFR及其下游的MAPK信號(JNK、p38和ERK)的表現量和增加caspase-3, 9的表現而促使CAR細胞走向凋亡。最後我們首次證實了熊果酸和薑黃素於順鉑耐性口腔癌上具有卓越的療效，其低副作用的天性將為未來治療耐藥性口腔癌上提供一個很好的選擇。

關鍵詞：熊果酸，西妥昔單抗，薑黃素，細胞凋亡，人類順鉑耐性口腔癌CAR細胞，表皮生長因子受體（EGFR），MAPK信號。

Oral squamous cell carcinoma (OSCC) is a cancer type that has high morbidity and mortality rates. It has chemotherapeutic resistance. Triterpenoid ursolic acid has been shown to exhibit various biological activities and anticancer effects. Previously, I have the the investigated acid’s effect on human cisplatin-resistant oral cancer CAR cells. Here I further explore the effects of ursolic acid on CAR cells. I found that ursolic acid inhibited CAR cell viability with MTT assay. Ursolic acid-induced cell death was mediated through a caspase-dependent pathway by checking with the pan-caspase inhibitor (z-VAD-fmk). Ursolic acid also increased the activities of caspase-3 and caspase-9 in CAR cells by the colorimetric assay. Specifically, ROS production and the loss of mitochondrial membrane potential (ΔΨm) detected by flow cytometry were found in the ursolic acid-treated CAR cells. The apoptosis-associated signaling showed that ursolic acid decreased the phosphorylation of AKT and BAD, as well as the protein levels of Bcl-2 and Bcl-xL, while it increased the expression of BAD and Bax in CAR cells. In summary, this study suggests a potential application of ursolic acid against drug-resistant oral carcinoma and oral anticancer efficacy in the near future.

Key words: Ursolic acid, apoptosis, AKT/BAD signaling, human cisplatin-resistant oral cancer CAR cells

Cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody (mAb), is the first novel targeted therapy for the treatment of patients with oral cancer. Cetuximab can combine with chemotherapeutic agents to prolong the overall survival rates in oral cancer patients. Curcumin is a traditional Chinese medicine, and it has been shown the growth inhibiting effects on oral cancer cells. However, there is no information regarding the combination of cetuximab and curcumin in drug-resistant oral cancer cells, and its underlying mechanism remains unclear. The purpose of the present study was to explore the oral anticancer effects of cetuximab combined with curcumin on cisplatin-resistant oral cancer CAR cell apoptosis in vitro. The results showed that combination treatment synergistically potentiated the effect of cetuximab and curcumin on suppression of cell viability and induction of apoptosis in CAR cells. Cetuximab and curcumin combination induced apoptosis and dramatically increased caspase-3 and caspase-9 activities compared to the action of alone agent. Combination treatment also markedly suppressed the protein levels of EGFR and mitogen-activated protein kinases (MAPKs) signaling (phosphorylation of ERK, JNK and p38). The results demonstrated that co-treatment with cetuximab and curcumin exerts synergistic oral anticancer effects on CAR cells through the suppression of the EGFR signaling by regulation of MAPK pathway.

Key word: cetuximab; curcumin; epidermal growth factor receptor (EGFR); MAPK signaling; cisplatin-resistant oral cancer CAR cells

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