A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment

Song, Jen‐Shin; Chang, Chih‐Chun; Wu, Chien-Huang; Dinh, Trinh Kieu; Jan, Jiing-Jyh; Huang, Kuan-Wei; Chou, Ming‐Chen; Shiue, Ting-Yun; Yeh, Kai-Chia; Ke, Yi‐Yu; Yeh, Teng‐Kuang; Ta, Yen‐Nhi Ngoc; Lee, Chia‐Jui; Huang, Jianguo; Sung, Yun‐Chieh; Shia, Kak‐Shan; Chen, Yunching

doi:10.1073/pnas.2015433118

Cited by 58 publications

(46 citation statements)

References 47 publications

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“…Preclinical studies using murine HCC models have suggested that targeting the the CCL2–CCR2 and CXCL12–CXCR4 axes may be a useful strategy to prevent tumorigenesis [ 188 , 189 ]. The use of BPRCX807, a highly selective CXCR4 antagonist, reduced TAM polarization and recruitment, and decreased angiogenesis, tumor metastasis, and proliferation through AKT- and ERK-signaling inhibition [ 190 ]. Recently, WSX1, a receptor subunit for IL-17, has been identified as a tumor-suppressor in hepatocytes, and was proposed as a potential target for immunotherapy [ 191 ].…”

Section: Targeting Cell Death and Tumor Microenvironmentmentioning

confidence: 99%

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

García-Pras

Fernández‐Iglesias

Gracia‐Sancho

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the contribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorigenesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution.

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Section: Targeting Cell Death and Tumor Microenvironmentmentioning

confidence: 99%

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

García-Pras

Fernández‐Iglesias

Gracia‐Sancho

et al. 2021

Cancers

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show abstract

“…BPRCX807, a selective and potent CXCR4 antagonist, recently demonstrated promising in vitro and in vivo effects on hepatocellular carcinoma mouse models. This molecule significantly suppressed primary tumor growth, prevented distant metastasis/cell migration, reduced angiogenesis, and normalised the immunosuppressive TME by reducing TAM infiltration, reprogramming TAMs toward an immunostimulatory phenotype and promoting cytotoxic T cell infiltration into the TME [135]. Notably, the integrated immune effects of CXCR4 antagonists were also observed in human patients with microsatellite stable colorectal and pancreatic tumors treated with 1 week of continuous infusion of AMD3100 [125].…”

Section: Cxcr4mentioning

confidence: 86%

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

Bule

Aguiar

Aires-da-Silva

et al. 2021

IJMS

120

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Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options.

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“…Notably, CXCR4 has either negligible or absent expression in normal cells, while it is overexpressed in the tumor cells close to normal cells (Chen et al, 2014). As mentioned earlier, the CXCR4/SDF-1 axis promotes tumor growth and attracts immune cells to the tumor sites; therefore, the blockade of this axis may ameliorate cancer metastasis (Mishra et al, 2016;Song et al, 2021). Our molecular docking results suggest that garlic compounds are bound to several key amino acids of CXCR4 and may have a beneficial impact in delaying the CXCR4 downstream mechanism during cancer progression.…”

Section: Figure 4 Amino Acid Residues and Interaction Types From Mole...mentioning

confidence: 96%

Computational Study of Garlic Compounds as Potential Anti-Cancer Agents for the Inhibition of CCR5 and CXCR4

Balqis¹,

Lukiati²,

Amin³

et al. 2022

CMUJNS

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Current cancer treatment methods are still inadequate due to the complexity of the cancer progression mechanism, which involves multiple genes, proteins, and signaling pathways. The discovery and validation of novel anticancer compounds remains challenging. Garlic has many medicinal properties that can combat various diseases. Organosulfur present in garlic has been shown to induce apoptosis in cancer cells; however, the underlying mechanism of action of non-organosulfur compounds from garlic in controlling cancer cells remains unclear. The present study aimed to analyze the efficacy of organosulfur and non-organosulfur compounds, including the flavonoid, terpenoid, and saponin groups, as inhibitors of C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4), which play significant roles in the progression of cancer. To determine the interactions between the active compounds of garlic and these receptors (CCR5 and CXCR4), molecular docking was performed using the PyRx v.0.8 software. Amino acid residues were analyzed and visualized using Biovia Discovery Studio and PyMol, respectively. Non-organosulfur compounds exhibited better results than the organosulfur compounds in binding affinity analysis. Tigogenin (from the saponin group) is considered to be a CCR5 inhibitor, while lupeol (from the terpenoid group) is considered to be a CXCR4 inhibitor. In conclusion, our results suggest that garlic compounds could be promising inhibitors of CCR5 and CXCR4, which are highly expressed in cancer. However, further research is needed to validate the in vitro and in vivo activities of garlic compounds for the inhibition of cancer progression. Keywords: Anticancer agents, CCR5, CXCR4, Garlic, Organosulfur compounds, Non-Organosulfur compounds]

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A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment

Cited by 58 publications

References 47 publications

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

Cell Death in Hepatocellular Carcinoma: Pathogenesis and Therapeutic Opportunities

Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

Computational Study of Garlic Compounds as Potential Anti-Cancer Agents for the Inhibition of CCR5 and CXCR4

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