Role of ubenimex as an anticancer drug and its synergistic effect with Akt inhibitor in human A375 and A2058 cells

Wang, Xiaoqing; Liu, Yang; Wu, Renyi; Guo, Feng; Zhang, Lijuan; Cui, Meng; Wu, Xiangyu; Zhang, Yongfei; Liu, Wei

doi:10.2147/ott.s157480

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…However, in another study, ubenimex showed its anti-leukaemic effect by inhibiting the phosphorylation of P38 43. In addition, ubenimex induced apoptosis and autophagic cell death, which was accompanied by increased phosphorylation of JNK 23. In our present study, we found that, as time passed, ERK1/2 was increasingly phosphorylated after ubenimex treatment.…”

Section: Discussionsupporting

confidence: 41%

“…Previous studies have demonstrated that ubenimex can induce not only apoptosis but also autophagic cell death in malignant melanoma and bladder cancer cells 22,23. In the present study, we directly detected autophagosome formation by transmission electron microscopy.…”

Section: Resultsmentioning

confidence: 69%

“…Previous reports have found that ubenimex shows cytotoxicity and suppresses cell proliferation in leukaemia cell lines,27 glioma,28 malignant melanoma and bladder cancer 22,23. In addition, ubenimex can also synergistically enhance the efficacy of anticancer drugs in many human tumour-derived cell lines, such as those from hepatocellular carcinoma and osteosarcoma 29–31.…”

Section: Discussionmentioning

confidence: 99%

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<p>Ubenimex induces apoptotic and autophagic cell death in rat GH3 and MMQ cells through the ROS/ERK pathway</p>

Wang¹,

Pang²,

Zhang³

et al. 2019

DDDT

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PurposeUbenimex, an aminopeptidase N (APN) inhibitor, is widely known for its use as an adjunct therapy for cancer therapy. However, in recent studies, it has also conferred antitumour effects in many cancers, but its anticancer mechanism is largely unknown. This study aims to investigate the specific anticancer activities and mechanisms of ubenimex in GH3 and MMQ cells.Materials and methodsIn this study, we investigated the anticancer effects of ubenimex in GH3 and MMQ cells. Cell viability and cell death were assessed by the Cell Counting Kit-8 kit (CCK-8) and a LIVE/DEAD cell imaging kit. Apoptosis and intracellular reactive oxygen species (ROS) generation were assessed by flow cytometry and fluorescence microscopy. Autophagosome formation was detected by transmission electron microscopy, and autophagic flux was measured with mRFP-GFP-LC3 adenoviral transfection. The protein expression level was detected by Western blotting.ResultsThe results revealed that treatment with ubenimex induced apoptotic and autophagic cell death in GH3 and MMQ cells, which resulted in decreased viability, an increased proportion of apoptotic cells, and autophagosome formation. Further experiments showed that ubenimex induced ROS generation and activated the ROS/ERK pathway. The ROS scavenger NAC could attenuate ubenimex-induced apoptosis and autophagy.ConclusionOur studies revealed that ubenimex exerted anticancer effects by inducing apoptotic and autophagic cell death in GH3 and MMQ cells, rendering it a possible effective adjunctive therapy for pituitary treatment.

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Section: Discussionsupporting

confidence: 41%

Section: Resultsmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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<p>Ubenimex induces apoptotic and autophagic cell death in rat GH3 and MMQ cells through the ROS/ERK pathway</p>

Wang¹,

Pang²,

Zhang³

et al. 2019

DDDT

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“…UBEN, a dipeptide analog, has been demonstrated to have diverse antitumor and immunomodulatory effects 36 , 37 . As UBEN is a typical PEPT1 substrate and appears to be transported into cells predominantly by PEPT1 38 , 39 , the effects of UBEN are mediated by this oligopeptide transport activity 18 .…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

Wang

Yang

et al. 2021

Cell Death Dis

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Human intestinal peptide transporter PEPT1 is commonly repressed in human colorectal cancer (CRC), yet its relationship with sensitivity to the common CRC treatment ubenimex has not previously been elucidated. In this study, we confirmed PEPT1 suppression in CRC using real-time quantitative polymerase chain reaction and western blotting and then investigated the underlying epigenetic pathways involved using bisulfite sequencing, chromatin immunoprecipitation, siRNA knockdown, and reporter gene assays. We found that PEPT1 transcriptional repression was due to both DNMT1-mediated DNA methylation of the proximal promoter region and HDAC1-mediated histone deacetylation, which blocked P300-mediated H3K18/27Ac at the PEPT1 distal promoter. Finally, the effects of the epigenetic activation of PEPT1 on the CRC response to ubenimex were evaluated using sequential combination therapy of decitabine and ubenimex both in vitro and in xenografts. In conclusion, epigenetic silencing of PEPT1 due to increased DNMT1 and HDAC1 expression plays a vital role in the poor response of CRC to ubenimex.

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“…APN has a critical role in controlling the differentiation and growth of cancer cells [ 19 ]. Inhibiting the expression or activity of APN has been attributed to a reduction in the migration, invasion, and proliferation of many types of cells [ 20 ], such as human clear cell ovarian carcinoma cells [ 21 ], human malignant melanoma cells, and human skin cancer cells [ 22 ]. Given that UBE enhances the tumor suppressive effect of PEM [ 13 ], in this study, we investigated the combined effect of these two drugs on lung adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Ubenimex Combined with Pemetrexed Upregulates SOCS1 to Inhibit Lung Adenocarcinoma Progression via the JAK2-STAT3 Signaling Pathway

Chen

et al. 2022

Disease Markers

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To study the effects of ubenimex (UBE) combined with pemetrexed (PEM) on lung adenocarcinoma cell behavior and its molecular mechanism, the tissue samples from lung adenocarcinoma patients who received PEM chemotherapy, those with PEM combined with UBE chemotherapy, and healthy volunteers were retrieved and analyzed. The expression levels of the suppressor of cytokine signaling 1 (SOCS1) in the human lung adenocarcinoma cancer cell lines A549 and PC-9 and tissues were detected by qRT-PCR. MTT assay was performed for cell proliferation. Cell apoptosis was detected by flow cytometry. Cell invasion ability was assessed using the Transwell assay. The expression levels of the JAK2/STAT3 signaling pathway proteins and apoptosis-related proteins were detected by Western blot. The antitumor effect of PEM combined with UBE was tested in nude mice using the tumor formation assay. Our results showed that UBE treatment, alone or combined with PEM, inhibited lung adenocarcinoma cell migration, invasion, and proliferation; promoted apoptosis; significantly increased the G0/G1-phase cell ratio; reduced the S-phase cell ratio; and inhibited the in vivo growth of tumor cells. UBE alone or in combination with PEM also inhibited the JAK2/STAT3 signaling pathway in lung adenocarcinoma cells. In addition, UBE combined with PEM therapy was associated with increased SOCS1 expression in patients’ serum and knocking down SOCS1 reversed the antitumor effects of UBE and PEM. Overall, combination therapy with UBE and PEM could inhibit the JAK2-STAT3 signaling pathway by upregulating SOCS1 expression to hinder the progression of lung adenocarcinoma cells.

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Role of ubenimex as an anticancer drug and its synergistic effect with Akt inhibitor in human A375 and A2058 cells

Cited by 7 publications

References 28 publications

<p>Ubenimex induces apoptotic and autophagic cell death in rat GH3 and MMQ cells through the ROS/ERK pathway</p>

<p>Ubenimex induces apoptotic and autophagic cell death in rat GH3 and MMQ cells through the ROS/ERK pathway</p>

Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

Ubenimex Combined with Pemetrexed Upregulates SOCS1 to Inhibit Lung Adenocarcinoma Progression via the JAK2-STAT3 Signaling Pathway

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