mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.

01 Mar 2021·Journal of Cellular and Molecular MedicineQ2 · MEDICINE

Potent antitumour of the mTORC1/2 dual inhibitor AZD2014 in docetaxel‐sensitive and docetaxel‐resistant castration‐resistant prostate cancer cells

Q2 · MEDICINE

ArticleOA

Author: Hu, Shuai ; Lv, Tianjing ; Yu, Wei ; Fan, Yu ; Li, Senmao ; Zhang, Cuijian ; Jin, Jie ; Sheng, Jindong ; Liu, Zhenhua ; Song, Yi

AbstractRecent studies indicate mammalian target of rapamycin (mTOR) may play an important role in PCa progression and drug resistance. Here, we investigated the effects of a novel mTORC1/C2 dual inhibitor, AZD2014, on naive and docetaxel (Doc)‐pre‐treated castration‐resistant PCa (CRPC) cells and explored its therapeutic potential in CRPCs. In the current study, AZD2014 has a greater inhibitory effect against 4EBP1 and AKT phosphorylation than rapamycin in CRPC cells and prevented the feedback activation of AKT signalling. Importantly, AZD2014 suppressed CRPC cell growth in vitro by suppressing proliferation, apoptosis, cell cycle arrest at G1 phase and autophagy to a greater extent than rapamycin. Moreover, AZD2014 was more efficacious than rapamycin in inhibiting migration, invasion and EMT progression in Doc‐sensitive and Doc‐resistant CRPC cells. Overall, AZD2014 showed significant antitumour effects. Thereby, the current study highlights a reliable theoretical basis for the clinical application of AZD2014 in both Doc‐sensitive and Doc‐resistant CRPCs.

01 Mar 2020·Photochemistry and PhotobiologyQ3 · BIOLOGY

Therapeutic Enhancement of Verteporfin‐mediated Photodynamic Therapy by mTOR Inhibitors

Q3 · BIOLOGY

Article

Author: Palasuberniam, Pratheeba ; Chen, Bin ; Kraus, Daniel

AbstractPhotodynamic therapy (PDT) with photosensitizer verteporfin is a clinically approved vascular disrupting modality that is currently in clinical trial for cancer treatment. In this study, we evaluated PDT in combination with either mTORC1 inhibitor rapamycin or mTORC1/C2 dual inhibitor AZD2014 for therapeutic enhancement in SVEC endothelial cells. Verteporfin‐PDT alone induced cell apoptosis by activating the intrinsic apoptotic pathway. However, it increased the expression of anti‐apoptotic protein MCL‐1 and the phosphorylation of S6, a downstream molecule of mTOR signaling. In contrast, mTOR inhibitors rapamycin and AZD2014 did not induce apoptosis in SVEC cells. They suppressed MCL‐1 expression and S6 phosphorylation and imposed a potent inhibition on cell proliferation. PDT in combination with mTOR inhibitors activated the intrinsic apoptotic pathway and resulted in increased apoptosis. Combination treatments also led to sustained inhibition of cell proliferation. Although AZD2014 was more effective for cell growth inhibition and PDT enhancement than rapamycin at the higher concentrations examined in the study, both inhibitors effectively enhanced PDT response, suggesting that inhibition of mTORC1 is crucial for PDT enhancement. Our results indicate that mTOR inhibitors mechanistically cooperate with PDT for enhanced cell death and sustained growth inhibition, supporting a combination approach for therapeutic enhancement.

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Metastatic breast cancer	Preclinical	US	NovoMedix LLC	-

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