Akt抑制劑MK-2206可提升taxol和cisplatin對卵巢癌細胞的毒殺性

Abstract

分子標靶藥物結合傳統細胞毒殺治療的應用在增強抗癌反應上似乎已成為新的治療策略。於人類的癌症中常見到PI3K/Akt/mTOR訊息途徑失常，且此訊息途徑異常也容易導致對化學治療產生抗藥性。MK-2206為一Akt抑制劑，可抑制癌細胞的增生。 於此，我們證實了MK-2206與cisplatin或taxol的合併治療可提升cisplatin或 taxol對卵巢癌細胞SKOV3 (Akt表現活化)和ES2 (Akt未表現活化)的作用。於taxol或cisplatin的治療中再給予MK-2206可加強抑制細胞增生的作用。合併治療可能是藉由抑制Akt及其下游受質4E-BP1和p70S6K的磷酸化，恢復因taxol或cisplatin所降低的p53表現，或減低Bcl-2蛋白來提升藥效。此外，我們於兩株卵巢癌細胞中都發現MK-2206可提高細胞內活性氧化物的生成，這可能會導致細胞凋零。另一方面，MK-2206可抑制BRCA1在cisplatin所造成的DNA損壞處聚集，這可能會使DNA無法修復。 所有的結果指出，Akt抑制劑MK-2206可能透過不同的機制來影響不同的卵巢癌細胞。不論癌細胞的Akt活化與否，MK-2206都可提升現在常用於臨床上之細胞毒殺劑之效用。

The application of molecular targeted agents in combination with traditional cytotoxic regimens seems to be a promising therapeutic strategy to increase antitumor response. Abnormalities in the PI3K/Akt/mTOR signaling pathway are common in human cancers and contribute to chemotherapy resistance. MK-2206 is an Akt inhibitor known to inhibit cancer cell proliferation. Here, we demonstrate an enhanced response to combination treatment of MK-2206 with either cisplatin or taxol in the ovarian cancer cell lines SKOV3 (with constitutively active Akt) and ES2 (with inactive Akt). Taxol or cisplatin followed by MK-2206 treatment synergistically inhibited cell proliferation. This combination was effective in promoting cell death by inhibiting Akt phosphorylation and downregulating its downstream effectors, p-4E-BP1 (Thr37/46) and p-p70S6K (Thr389), in SKOV3 cells, restoring p53 level which was downregulated after taxol or cisplatin treatment in ES2 cells, and downregulating pro-survival Bcl-2 protein in both SKOV3 cells and ES2 cells. In addition, we found that intracellular ROS generation was increased in both ovarian cancer cell lines after MK-2206 treatment, that may lead to apoptosis. Moreover, MK-2206 could suppress BRCA1 foci formation at DNA damage sites induced by cisplatin that may affect DNA repair. The overall results indicate that Akt inhibitor MK-2206 may augment the efficacy of existing cytotoxic agents through different mechanisms in either Akt active or inactive ovarian cancer cells.