Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and metastasis-inhibiting effects on breast cancer cells

Liu, Yuan; Liu, Jun; He, Wenhui; Bao, Youmei; Sheng, Lei; Zou, Chunyang; Hu, Baichun; Ge, Wentao; Liu, Yang; Wang, Jian; Lin, Bin; Li, Yanchun; Ma, Enlong

doi:10.1016/j.bioorg.2018.11.025

Cited by 10 publications

(6 citation statements)

References 32 publications

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“…Moreover, asperphenidine F1, was the only active candidate against the pancreas cell line, suggesting the nicotinic acid analogs being more active than the benzoic acid analogs. Although our cytotoxicity results for asperphenamates F and Y, as well as asperphenidine F1 are comparable to the previously published data, none of them show improved bioactivity compared to synthetic asperphenamate derivatives (Li et al, 2012;Yuan et al, 2012Yuan et al, , 2018Yuan et al, , 2019Yuan et al, , 2020Liu et al, 2016Liu et al, , 2018.…”

Section: Discussionsupporting

confidence: 85%

“…Additionally, the compound has also been isolated in trace amounts from a number of unrelated plant species (Wu et al, 2004;Dang et al, 2014;Zhou et al, 2017;Bunteang et al, 2018;Caridade et al, 2018), suggesting endophytic fungi being the actual producers, rather than the plants. Although asperphenamate is mainly known for its antitumour activity and immense synthetic chemists interest in asperphenamate backbone modification (Li et al, 2012;Yuan et al, 2012Yuan et al, , 2018Yuan et al, , 2019Yuan et al, , 2020Liu et al, 2016), recent studies have also shown asperphenamate to be a potential neuroinflamatory inhibitor (Zhou et al, 2017), and to possess anti-HIV (Bunteang et al, 2018) and antidiabetic (Del Valle et al, 2016) properties. In recent years, a handful of new natural analogs have been isolated, namely Asperphenamates B (4) and C (5) (Liu et al, 2018), and 4-OMe-asperphenamate (Zheng et al, 2013;Ratnaweera et al, 2016) (6) from filamentous fungi.…”

Section: Introductionmentioning

confidence: 99%

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Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

et al. 2021

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Asperphenamate is a small peptide natural product that has gained much interest due to its antitumor activity. In the recent years numerous bioactive synthetic asperphenamate analogs have been reported, whereas only a handful of natural analogs either of microbial or plant origin has been discovered. Herein we describe a UHPLC-HRMS/MS and amino acid supplement approach for discovery and design of novel asperphenamate analogs. Chemical analysis of Penicillium astrolabium, a prolific producer of asperphenamate, revealed three previously described and two novel asperphenamate analogs produced in significant amounts, suggesting a potential for biosynthesis of further asperphenamate analogs by varying the amino acid availability. Subsequent growth on proteogenic and non-proteogenic amino acid enriched media, revealed a series of novel asperphenamate analogs, including single or double amino acid exchange, as well as benzoic acid exchange for nicotinic acid, with the latter observed from a natural source for the first time. In total, 22 new asperphenamate analogs were characterized by HRMS/MS, with one additionally confirmed by isolation and NMR structure elucidation. This study indicates an extraordinary nonribosomal peptide synthetase (NRPS) flexibility based on substrate availability, and therefore the potential for manipulating and designing novel peptide natural products in filamentous fungi.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

et al. 2021

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“…Understanding the molecular mechanisms of CLN3, GBA, and LAPTM4B in liver cancer cells may help to develop new therapeutic targets for liver cancer. In addition, Cathepsin A (CTSA), a lysosome-encapsulated cellular proteases, its abnormal expression promotes tumor growth and metastasis 23 , 24 . Zhao et al 47 also reported that CTSA was overexpressed and associated with the carcinogenesis of liver cancer.…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of a novel lysosomal signature for hepatocellular carcinoma prognosis, diagnosis, and therapeutic decision-making

Chen,

Gao,

et al. 2023

Sci Rep

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Lysosomes is a well-recognized oncogenic driver and chemoresistance across variable cancer types, and has been associated with tumor invasiveness, metastasis, and poor prognosis. However, the significance of lysosomes in hepatocellular carcinoma (HCC) is not well understood. Lysosomes-related genes (LRGs) were downloaded from Genome Enrichment Analysis (GSEA) databases. Lysosome-related risk score (LRRS), including eight LRGs, was constructed via expression difference analysis (DEGs), univariate and LASSO-penalized Cox regression algorithm based on the TCGA cohort, while the ICGC cohort was obtained for signature validation. Based on GSE149614 Single-cell RNA sequencing data, model gene expression and liver tumor niche were further analyzed. Moreover, the functional enrichments, tumor microenvironment (TME), and genomic variation landscape between LRRSlow/LRRShigh subgroup were systematically investigated. A total of 15 Lysosomes-related differentially expressed genes (DELRGs) in HCC were detected, and then 10 prognosis DELRGs were screened out. Finally, the 8 optimal DELRGs (CLN3, GBA, CTSA, BSG, APLN, SORT1, ANXA2, and LAPTM4B) were selected to construct the LRRS prognosis signature of HCC. LRRS was considered as an independent prognostic factor and was associated with advanced clinicopathological features. LRRS also proved to be a potential marker for HCC diagnosis, especially for early-stage HCC. Then, a nomogram integrating the LRRS and clinical parameters was set up displaying great prognostic predictive performance. Moreover, patients with high LRRS showed higher tumor stemness, higher heterogeneity, and higher genomic alteration status than those in the low LRRS group and enriched in metabolism-related pathways, suggesting its underlying role in the progression and development of liver cancer. Meanwhile, the LRRS can affect the proportion of immunosuppressive cell infiltration, making it a vital immunosuppressive factor in the tumor microenvironment. Additionally, HCC patients with low LRRS were more sensitive to immunotherapy, while patients in the high LRRS group responded better to chemotherapy. Upon single-cell RNA sequencing, CLN3, GBA, and LAPTM4B were found to be specially expressed in hepatocytes, where they promoted cell progression. Finally, RT-qPCR and external datasets confirmed the mRNA expression levels of model genes. This study provided a direct links between LRRS signature and clinical characteristics, tumor microenvironment, and clinical drug-response, highlighting the critical role of lysosome in the development and treatment resistance of liver cancer, providing valuable insights into the prognosis prediction and treatment response of HCC, thereby providing valuable insights into prognostic prediction, early diagnosis, and therapeutic response of HCC.

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“…Its overexpression and increased enzymatic activity have been observed across various breast cancer subtypes and is a prognostic factor for (disease free) survival of breast cancer patients [56,57,61,66,67,95,[100][101][102]. Cathepsin L has been shown to play a major role in the process of lung metastasis [101,103,104]. In vitro ribonucleic acid (RNA) interference and pharmacological inhibition studies demonstrated that breast cancer cells use cathepsin L to enhance their proliferative, invasive, and migratory capacity by degrading ECM components [101][102][103][104][105][106].…”

Section: Cathepsin Lmentioning

confidence: 99%

“…Cathepsin L has been shown to play a major role in the process of lung metastasis [101,103,104]. In vitro ribonucleic acid (RNA) interference and pharmacological inhibition studies demonstrated that breast cancer cells use cathepsin L to enhance their proliferative, invasive, and migratory capacity by degrading ECM components [101][102][103][104][105][106]. This effect was also observed in vivo, as mice injected with cathepsin L knockdown breast cancer cells or treated with a selective cathepsin L inhibitor exhibited significantly smaller tumors compared to the controls with functional cathepsin L [101,103,105].…”

Section: Cathepsin Lmentioning

confidence: 99%

Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

et al. 2022

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The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.

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Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and metastasis-inhibiting effects on breast cancer cells

Cited by 10 publications

References 32 publications

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

Mass Spectrometry Guided Discovery and Design of Novel Asperphenamate Analogs From Penicillium astrolabium Reveals an Extraordinary NRPS Flexibility

Construction and validation of a novel lysosomal signature for hepatocellular carcinoma prognosis, diagnosis, and therapeutic decision-making

Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

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