近期本研發團隊發表了以白蛋白微氣泡對比劑包覆順鉑(Cisplatin, CDDP)搭配超音波能量施打，進而促進頭頸腫瘤血管內通透度開啟而釋放藥物，並降低整體細胞毒性。然而，在CDDP治療過程中產生腫瘤的抗藥性是其使用的主要限制，有人提出JNK訊息傳遞在CDDP治療中是一種重要的促凋亡因子，但也與提升以CDDP為基礎的化療抗藥性有關。他汀類（Statins）藥物則是被廣泛地用於抑制血脂膽固醇生成，以減少心血管疾病之風險。隨著研究發展，科學家發現他汀類藥物亦具有抗癌的特性，抑制JNK信號傳遞，進而抑制癌細胞生長、促凋亡、加強癌細胞對於放射線治療的敏感性等等。現今有許多研究將CDDP結合他汀類藥物治療癌症，可能有助於克服其化學抗藥性，此外，一些早期研究發現，辛伐他汀 (Simvastatin)以及洛伐他汀 (Lovastatin)對CDDP所誘發的腎損傷具保護作用。本論文研究選用阿托伐他汀 (Atorvastatin)與CDDP單獨或是結合使用治療頭頸癌細胞，探討其最佳協同作用 (synergism) 抑制癌細胞之組合濃度。並以超音波誘發包覆CDDP之白蛋白微氣泡 (MBs)產生的穴蝕效應結合阿托伐他汀提升藥物於癌細胞的治療效果，並降低CDDP使用劑量，減少其副作用以及抗藥性。
WST-1細胞增殖試驗結果中，未經超音波施打前，CDDP包覆於MBs 組對下咽癌細胞毒性效果不佳，但經超音波施打與加入 Atorvastatin後整體毒殺能力大幅提升，平均細胞存活率下降 30 % (p<0.001);而相較傳統使用單獨抗癌藥物CDDP，CDDP-MBs + Atorvastatin結合超音波平均細胞存活率下降 20 %。在流式細胞儀實驗結果中，CDDP-MBs + Atorvastatin結合超音波明顯降低了GSH的含量，從而增加活性氧自由基的產生，將導致去氧核醣核酸的損傷，同時增強癌細胞對 CDDP的敏感性，進而解決CDDP抗藥性的問題。故綜合以上 CDDP-MBs + Atorvastatin結合超音波，可以顯著達治療癌症之效果，並降低CDDP化療藥物的使用劑量與抗藥性，減少 CDDP 所引起的副作用。

In our previous study, ultrasound mediated drug loaded microbubbles (US-MBs) was as a tool to increase the local intra-tumoral CDDP level, while decreasing systemic CDDP cytotoxicity in an experimental animal model of head and neck cancer. Statins, recently widely used to inhibit the production of cholesterol, which reduces the risk of cardiovascular disease, was also reported that it has properties of anti-cancer, including inhibiting the proliferation of cancer cells, promoting apoptosis, and enhancing the sensitivity of cancer cells to radiation therapy through inhibition of the JNK-signaling pathway. Since inhibition of JNK activation is a major mechanism behind tumor resistance to cisplatin. Therefore, the addition of statins to CDDP might help overcome any chemoresistance. Moreover, some previous studies investigated the protective effect of simvastatin and rosuvastatin on CDDP-induced nephrotoxicity.
In our study in vitro, CDDP-MBs + atorvastatin can increase 30 % cell toxicity after ultrasound irradiation (p<0.001). Compared to traditional treatment of using CDDP alone, Co-administration of CDDP-MBs and atorvastatin combined with US can increase 20 % cell toxicity. Furthermore, by flow cytometry assay, Co-administration of CDDP-MBs and atorvastatin combined with US can reduce the value of GSH, and increase the production of free radicals to destroy the structure of DNA. These enhance the sensitivity of cancer cells to CDDP, and overcome CDDP resistance problem. In conclusion, co-administration of CDDP-MBs and atorvastatin combined with US can improve anticancer effect significantly, overcome CDDP resistance, and reduce the side effects caused by CDDP.

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