scholarly journals Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

2022 ◽  
Vol 79 (1) ◽  
Author(s):  
Ana Mitrović ◽  
Janja Završnik ◽  
Georgy Mikhaylov ◽  
Damijan Knez ◽  
Urša Pečar Fonović ◽  
...  

AbstractNew therapeutic targets that could improve current antitumor therapy and overcome cancer resistance are urgently needed. Promising candidates are lysosomal cysteine cathepsins, proteolytical enzymes involved in various critical steps during cancer progression. Among them, cathepsin X, which acts solely as a carboxypeptidase, has received much attention. Our results indicate that the triazole-based selective reversible inhibitor of cathepsin X named Z9 (1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-((4-isopropyl-4H-1,2,4-triazol-3-yl)thio)ethan-1-one) significantly reduces tumor progression, both in vitro in cell-based functional assays and in vivo in two independent tumor mouse models: the FVB/PyMT transgenic and MMTV-PyMT orthotopic breast cancer mouse models. One of the mechanisms by which cathepsin X contributes to cancer progression is the compensation of cathepsin-B activity loss. Our results confirm that cathepsin-B inhibition is compensated by an increase in cathepsin X activity and protein levels. Furthermore, the simultaneous inhibition of both cathepsins B and X with potent, selective, reversible inhibitors exerted a synergistic effect in impairing processes of tumor progression in in vitro cell-based assays of tumor cell migration and spheroid growth. Taken together, our data demonstrate that Z9 impairs tumor progression both in vitro and in vivo and can be used in combination with other peptidase inhibitors as an innovative approach to overcome resistance to antipeptidase therapy.

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
You Hu ◽  
Bin Yi ◽  
Xin Chen ◽  
Lu Xu ◽  
Xiaojun Zhou ◽  
...  

Gastric cancer (GC) is among the most prevalent causes of cancer-related death globally. MiR-223 has been implicated in a variety of cellular mechanisms linked to cancer progression. However, the miR-223 expressions and its function in GC are unknown. We discovered that miR-223 expression was raised in GC tissues in comparison with nearby normal tissues in this investigation. Additionally, multiplied miR-223 expression was strongly linked with TNM stage ( p = 0.022 ), live metastasis ( p = 0.004 ),lymph node metastasis ( p = 0.004 ),and Borrmann type and was associated with an unfavorable prognostic for patients with GC. Furthermore, suppressing miR-223 significantly increased cell death and prevented cell migration and invasion in vitro. Additionally, miR-223 silencing decreased tumor development in vivo. Additionally, we discovered that miR-223 enhanced GC development by specifically targeting RhoB. In summary, our findings reveal that miR-223 increases tumor progression in GC by targeting RhoB, suggesting that it could serve to be a potential biomarker for the prediction of the disease.


2021 ◽  
Author(s):  
David G DeNardo ◽  
Chong Zuo ◽  
John M. Baer ◽  
Brett L. Knolhoff ◽  
Jad I. Belle ◽  
...  

Tumor-associated macrophages (TAMs) are involved in many aspects of cancer progression and correlate with poor clinical outcomes in many cancer types, including pancreatic ductal adenocarcinomas (PDACs). Previous studies have shown that TAMs can populate PDAC tumors not only by monocyte recruitment but also by local proliferation. However, the impact local proliferation might have on macrophage phenotype and cancer progression is unknown. Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro systems to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also drive response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.


2021 ◽  
Vol 27 ◽  
Author(s):  
Vibha Rani ◽  
Dhananjay Yadav ◽  
Neha Atale

Background: Cancer is a wide range cellular level disease that occurs when cells go through uncontrolled division and growth. The mechanisms by which the cells undergo metastasis are complex and involve many interactions between the tumor cells and their cellular environment. Matrix metalloproteinases (MMPs) have been found to over-express at various stages of tumor progression and their inhibition using MMP inhibitors has been a subject of potential therapy against cancer. Objective: This review discusses recent research in MMP inhibitors (MMPI) used for preventing tumor progression. Methods: In this review, we explored the role of MMPs in cancer progression and summarized the current developments in MMPIs, their role in cancer suppression in in vitro and in vivo studies and their evaluation in clinical trials from the current research data. Results: MMPIs have shown to be very successful in in vitro models, cell lines and in some in vivo studies. Unfortunately, their efficacy in clinical trials has been found to be hit and miss. Recent studies have shown that the novel delivery approaches of MMP inhibitors may enhance their therapeutic effects towards the prevention of cancer. Conclusion: In this review, we presented different MMP inhibitors, their performance at different stages of models - in vitro, in vivo, small animal models and eventually clinical trials. We provide newer methods of MMPI delivery that may be better targeted to suppress only specific MMPs and avoid toxic side-effects in healthy cells.


2018 ◽  
Vol 19 (12) ◽  
pp. 3798 ◽  
Author(s):  
Giulia Fianco ◽  
Claudia Contadini ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Venturina Stagni ◽  
...  

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.


2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jayna J Mistry ◽  
Charlotte Hellmich ◽  
Amelia Lambert ◽  
Jamie A Moore ◽  
Aisha Jibril ◽  
...  

AbstractAcute myeloid leukemia (AML) remains an incurable malignancy despite recent advances in treatment. Recently a number of new therapies have emerged for the treatment of AML which target BCL-2 or the membrane receptor CD38. Here, we show that treatment with Venetoclax and Daratumumab combination resulted in a slower tumor progression and a reduced leukemia growth both in vitro and in vivo. These data provide evidence for clinical evaluation of Venetoclax and Daratumumab combination in the treatment of AML.


Oncotarget ◽  
2015 ◽  
Vol 6 (22) ◽  
pp. 19027-19042 ◽  
Author(s):  
Bojana Mirković ◽  
Boštjan Markelc ◽  
Miha Butinar ◽  
Ana Mitrović ◽  
Izidor Sosič ◽  
...  

2020 ◽  
Author(s):  
Kai Liu ◽  
Huiying Hu ◽  
Huanyu Jiang ◽  
Haidong Zhang ◽  
Shanchun Gong ◽  
...  

Abstract Tumor progression and metastasis are still major burdens for head and neck squamous cell carcinoma (HNSCC). Runt-related transcription factor 1 (RUNX1) are involved in aggressive phenotypes in several cancers, while the molecular role of RUNX1 underlying cancer progression and metastasis of HNSCC remains largely unknown. In our study, RUNX1 expression was increased with disease progression in patients with HNSCC. The silencing of RUNX1 significantly decelerated the malignant progression of HNSCC cells, reduced Osteopontin (OPN) expression in vitro, and weakened the tumorigenicity of HNSCC cells in vivo. Moreover, we demonstrated that RUNX1 activated the MAPK signaling by directly binding to the promoter of OPN in tumor progression and metastasis of HNSCC. Our results may provide new insight into the mechanisms underlying the role of RUNX1 in tumor progression and metastasis and reveal the potential therapeutic target in HNSCC.


2018 ◽  
Vol 49 (1) ◽  
pp. 87-100 ◽  
Author(s):  
Xuxing Shen ◽  
Hua Bai ◽  
Huayuan Zhu ◽  
Qing Yan ◽  
Ye Yang ◽  
...  

Background/Aims: Long non-coding RNA maternally expressed gene 3 (MEG3) has been reported to play an essential role in cancer progression and metastasis. However, the overall biological role and regulatory mechanism of MEG3 in multiple myeloma (MM) development and progression remains largely ill-defined. Methods: MEG3 and miR-181a expression of MM patients were analyzed by publicly available MM data sets. Cell counting kit-8 and flow cytometry analysis were used to identify the function of MEG3 on MM in vitro. Additionally, we conducted tumor formation experiments in mice models to explain the role of MEG3 on MM in vivo. Then, several mechanism experiments, including dual-luciferase reporter assay and RNA immunoprecipitation were performed to evaluate the emulative relationship between MEG3 and miR-181a. Results: In this research, we found that MEG3 was downregulated in MM patients, which was linked with tumor progression. In addition, we demonstrated that miR-181a was overexpressed in MM patients in consistent with its cancer-promoting function. Importantly, several mechanism experiments revealed that MEG3, acting as an endogenous competitive RNA, could contend with miR-181a to inhibit tumor progression. Furthermore, as the target mRNA of miR-181a, homeobox gene A11(HOXA11) could be positively regulated by MEG3 through sponging miR-181a competitively in vitro. Conclusion: Our present work supplies the first discovery of a MEG3/miR-181a/HOXA11 regulatory network in MM and highlights that MEG3 may serve as a promising target for MM therapy in the future.


2018 ◽  
Vol 18 (2) ◽  
pp. 156-165 ◽  
Author(s):  
Jiaqiang Wang ◽  
Chien-shan Cheng ◽  
Yan Lu ◽  
Xiaowei Ding ◽  
Minmin Zhu ◽  
...  

Background: Propofol, a widely used intravenous anesthetic agent, is traditionally applied for sedation and general anesthesia. Explanation: Recent attention has been drawn to explore the effect and mechanisms of propofol against cancer progression in vitro and in vivo. Specifically, the proliferation-inhibiting and apoptosis-inducing properties of propofol in cancer have been studied. However, the underlying mechanisms remain unclear. Conclusion: This review focused on the findings within the past ten years and aimed to provide a general overview of propofol's malignance-modulating properties and the potential molecular mechanisms.


Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.


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