Indinavir為高效抗反轉錄病毒治療(Highly Active Anti-Retroviral Therapy, HAART)的一種 HIV蛋白酶抑製劑用於治療 HIV / AIDS患者，有趣的是，一些研究結果認為 Indinavir是一個具有潛力的抗癌藥物。然而，其確切的抗癌作用機制尚不清楚。在本研究中，我們的目的是去探討 Indinavir應用在治療人類癌症的可能性，並了解其在癌症細胞中的作用分子機制。

在我們的研究中發現當 Indinavir在濃度介於180 - 285 μM的條件下 MCF-7（caspase-3缺陷，野生型p53表達）、MDA-MB-231、SK-BR-3（caspase-3和突變型p53表達）、KB（非表達MDR-1）和KB-VIN10（表達MDR-1）癌細胞中具有促細胞死亡的作用 ，有趣的是，在分子層次上，我們發現在 MDA-MB-231和 SK-BR-3細胞中 Indinavir會誘導 ROS依賴性DNA損傷、G2 / M期的細胞週期停滯、典型細胞凋亡，但是在MCF-7細胞則不然。 令人驚訝的是，在分析RNAseq產生的KEGG分析結果和西方墨點法的結果發現在MCF-7細胞中其細胞死亡與典型細胞凋亡無關，但類似於壞死樣凋亡的分子變化。

綜合以上結果，我們的研究結果表明 Indinavir在不同的癌細胞中表現出不同的抗癌作用機制。了解 Indinavir在不同分子圖譜的癌細胞中的分子功能上的差異可為選擇其他潛在治療藥物提供重要信息，這些治療藥物可與 Indinavir一起用於未來癌症治療的合併療法中。

Indinavir is a HIV-protease inhibitor used as a highly active antiretroviral therapy (Highly Active Anti-Retroviral Therapy, HAART) for HIV/AIDS patients. Interestingly, findings of a few studies suggested Indinavir as a potential anti-cancer agent. However, the underlying anti-cancer mechanism of actions remains unclear. In this study, we aim to evaluate the possibility of using Indinavir in treating human cancers with different molecular profiles and also to uncover its molecular mechanism of actions in cancer cells.

In the current study, we found that Indinavir exhibits pro-cell death effects in MCF7 (caspase-3 deficient, wild-type p53 expressing), MDA-MB-231 and SK-BR-3 (caspase-3 and mutant p53 expressing), KB (MDR-1 non-expressing), and KB-VIN10 (KB-derived MDR-1 expressing) cancer cells at concentrations from 180 - 285 μM. Intriguingly, at the cellular and molecular levels, Indinavir induced ROS-dependent DNA damage, cell cycle arrested at the G2/M phase, and canonical apoptosis in MDA-MB-231 and SK-BR-3, but not in MCF-7 cells. Surprisingly, results of the KEGG enrichment analysis on data generated from RNAseq and the Western blot analysis showed that the same treatment induced canonical apoptosis-unrelated, but necroptosis-like, molecular changes in MCF7 cells.

Taken together, our findings indicate that Indinavir exhibits differential anti-cancer mechanism of actions in different cancer cells. Understanding the differential molecular functions of Indinavir in cancer cells with different molecular profiles may provide important information for selecting other potential therapeutic agents that can be used together with Indinavir as combination therapy for cancer treatment in the future.

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