Hemiasterlin (R)(S)(S)-BF65增強PI3K/AKT抑制劑抑制細胞遷移的效果

Abstract

癌細胞由原發性腫瘤擴散至不相鄰的其他器官稱之為腫瘤轉移。而上皮間質轉換 (Epithelial–mesenchymal transition, EMT) 是癌細胞轉移的早期步驟，其作用使得癌細胞間的聯繫鬆散，進一步誘發癌細胞遷移和侵入至其他器官。腫瘤轉移是造成癌症治療失敗和病患死亡的常見因素，因此，抑制腫瘤轉移被視為癌症治療一項重要的議題。 在女性中，卵巢癌與乳癌是排名前兩位致死率最高的癌症，在此類癌症的治療上，合併藥物治療的概念扮演了重要的角色，合併治療不僅能夠減少藥物的毒性和所造成的副作用，甚至可以增加對抗癌細胞的效果。在本研究中，我們利用傷口癒合(畫痕法)、 transwell 遷移和侵入實驗發現海綿胜肽成分hemiasterlin的全合成抗微管劑 (R)(S)(S)-BF65 能夠提升PI3K/mTOR 雙重抑制劑NVP-BEZ235在癌細胞中造成抑制移動能力的效果，而此效果同時在人類卵巢癌細胞株SKOV3和人類乳癌細胞株 MDA-MB-231被觀察到。更進一步發現，合併使用 NVP-BEZ235 和 (R)(S)(S)-BF65 能夠調控EMT相關的蛋白表現量，例如：E-cadherin、Slug、Snail等，這些蛋白表現量變化也被證明參與在PI3K/AKT/GSK3 的一系列訊號路徑中。 總而言之， NVP-BEZ235 和 (R)(S)(S)-BF65 合併使用在抑制癌細胞移行的能力上顯現出協同的效果。因此，這兩種藥物合併使用可視為對於抑制癌細胞轉移的潛在策略。

Tumor metastasis is the spread of tumor cells from primary tumor site to another organ which is not directly connected. Epithelial–mesenchymal transition (EMT), an early step of cancer metastasis, allows cancer cells lose connections with neighboring cells, thereby inducing cellular migration and invasion. Metastasis has been a big issue to cancer therapy and causes therapeutic failure and the death of patients. Therefore, inhibiting cancer metastasis is a major concern of cancer treatment. Ovarian cancer and breast cancer are the top two lethal cancers among woman. The concept of combination treatment plays an essential role in cancer therapy to reduce the toxicity and side effects, and to enhance the anti-cancer effect. In this study, we found that (R)(S)(S)-BF65 could enhance cell motility inhibition effect of NVP-BEZ235, a PI3K/mTOR dual inhibitor, using wound healing migration, transwell migration and invasion assays, and this effect appeared in both human ovarian cancer cell line SKOV3 and human breast cancer cell line MDA-MB-231. Moreover, the combination of NVP-BEZ235 and (R)(S)(S)-BF65 regulated EMT associated biomarkers, such as E-cadherin, Slug and Snail, which are involved in the PI3K/AKT/GSK3beta signaling pathway. In conclusion, NVP-BEZ235 and (R)(S)(S)-BF65 synergistically inhibit migration ability of cancer cells. Thus, this combination treatment may be a potential strategy against cancer metastasis.