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18 pages, 5557 KiB

Open AccessArticle

E7050 Suppresses the Growth of Multidrug-Resistant Human Uterine Sarcoma by Inhibiting Angiogenesis via Targeting of VEGFR2-Mediated Signaling Pathways

by Tsung-Teng Huang, Chuan-Mu Chen, Song-Shu Lin, Ying-Wei Lan, Hsu-Chen Cheng, Kong-Bung Choo, Ching-Chiung Wang, Tse-Hung Huang and Kowit-Yu Chong

Int. J. Mol. Sci. 2023, 24(11), 9606; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119606 - 31 May 2023

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Abstract

E7050 is an inhibitor of VEGFR2 with anti-tumor activity; however, its therapeutic mechanism remains incompletely understood. In the present study, we aim to evaluate the anti-angiogenic activity of E7050 in vitro and in vivo and define the underlying molecular mechanism. It was observed [...] Read more.

E7050 is an inhibitor of VEGFR2 with anti-tumor activity; however, its therapeutic mechanism remains incompletely understood. In the present study, we aim to evaluate the anti-angiogenic activity of E7050 in vitro and in vivo and define the underlying molecular mechanism. It was observed that treatment with E7050 markedly inhibited proliferation, migration, and capillary-like tube formation in cultured human umbilical vein endothelial cells (HUVECs). E7050 exposure in the chick embryo chorioallantoic membrane (CAM) also reduced the amount of neovessel formation in chick embryos. To understand the molecular basis, E7050 was found to suppress the phosphorylation of VEGFR2 and its downstream signaling pathway components, including PLCγ1, FAK, Src, Akt, JNK, and p38 MAPK in VEGF-stimulated HUVECs. Moreover, E7050 suppressed the phosphorylation of VEGFR2, FAK, Src, Akt, JNK, and p38 MAPK in HUVECs exposed to MES-SA/Dx5 cells-derived conditioned medium (CM). The multidrug-resistant human uterine sarcoma xenograft study revealed that E7050 significantly attenuated the growth of MES-SA/Dx5 tumor xenografts, which was associated with inhibition of tumor angiogenesis. E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders. Full article

(This article belongs to the Special Issue Development of New Molecular Targets and Therapeutic Approaches against Multidrug-Resistant Cancers)

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18 pages, 3409 KiB

Open AccessArticle

Blockade of c-Met-Mediated Signaling Pathways by E7050 Suppresses Growth and Promotes Apoptosis in Multidrug-Resistant Human Uterine Sarcoma Cells

by Tsung-Teng Huang, Chuan-Mu Chen, Ying-Wei Lan, Song-Shu Lin, Kong-Bung Choo and Kowit-Yu Chong

Int. J. Mol. Sci. 2022, 23(23), 14884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314884 - 28 Nov 2022

Cited by 2 | Viewed by 1465

Abstract

E7050 is a potent inhibitor of c-Met receptor tyrosine kinase and has potential for cancer therapy. However, the underlying molecular mechanism involved in the anti-cancer property of E7050 has not been fully elucidated. The main objective of this study was to investigate the [...] Read more.

E7050 is a potent inhibitor of c-Met receptor tyrosine kinase and has potential for cancer therapy. However, the underlying molecular mechanism involved in the anti-cancer property of E7050 has not been fully elucidated. The main objective of this study was to investigate the anti-tumor activity of E7050 in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells in vitro and in vivo, and to define its mechanisms. Our results revealed that E7050 reduced cell viability of MES-SA/Dx5 cells, which was associated with the induction of apoptosis and S phase cell cycle arrest. Additionally, E7050 treatment significantly upregulated the expression of Bax, cleaved PARP, cleaved caspase-3, p21, p53 and cyclin D1, while it downregulated the expression of survivin and cyclin A. On the other hand, the mechanistic study demonstrated that E7050 inhibited the phosphorylation of c-Met, Src, Akt and p38 in HGF-stimulated MES-SA/Dx5 cells. Further in vivo experiments showed that treatment of athymic nude mice carrying MES-SA/Dx5 xenograft tumors with E7050 remarkably suppressed tumor growth. E7050 treatment also decreased the expression of Ki-67 and p-Met, and increased the expression of cleaved caspase-3 in MES-SA/Dx5 tumor sections. Therefore, E7050 is a promising drug that can be developed for the treatment of multidrug-resistant uterine sarcoma. Full article

(This article belongs to the Special Issue Development of New Molecular Targets and Therapeutic Approaches against Multidrug-Resistant Cancers)

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Review

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14 pages, 1412 KiB

Open AccessReview

Role of Midkine in Cancer Drug Resistance: Regulators of Its Expression and Its Molecular Targeting

by Minakshi Saikia, Nathan Cheung, Abhay Kumar Singh and Vaishali Kapoor

Int. J. Mol. Sci. 2023, 24(10), 8739; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108739 - 14 May 2023

Cited by 4 | Viewed by 2251

Abstract

Molecules involved in drug resistance can be targeted for better therapeutic efficacies. Research on midkine (MDK) has escalated in the last few decades, which affirms a positive correlation between disease progression and MDK expression in most cancers and indicates its association with multi-drug [...] Read more.

Molecules involved in drug resistance can be targeted for better therapeutic efficacies. Research on midkine (MDK) has escalated in the last few decades, which affirms a positive correlation between disease progression and MDK expression in most cancers and indicates its association with multi-drug resistance in cancer. MDK, a secretory cytokine found in blood, can be exploited as a potent biomarker for the non-invasive detection of drug resistance expressed in various cancers and, thereby, can be targeted. We summarize the current information on the involvement of MDK in drug resistance, and transcriptional regulators of its expression and highlight its potential as a cancer therapeutic target. Full article

(This article belongs to the Special Issue Development of New Molecular Targets and Therapeutic Approaches against Multidrug-Resistant Cancers)

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