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Dual anti-angiogenic and anti-metastatic activity of myriocin synergistically enhances the anti-tumor activity of cisplatin

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Abstract

Purpose

Tumor microenvironment consists of various kind of cells, forming complex interactions and signal transductions for tumor growth. Due to this complexity, targeting multiple kinases could yield improved clinical outcomes. In this study, we aimed to investigate the potential of myriocin, from Mycelia sterilia, as a novel dual-kinase inhibitor and suggest myriocin as a candidate for combined chemotherapy.

Methods

We initially evaluated the anti-tumor and anti-metastatic effect of myriocin in mouse allograft tumor models. We examined the effects of myriocin on angiogenesis and tumor vasculature using in vitro, in vivo, and ex vivo models, and also tested the anti-migration effect of myriocin in in vitro models. Next, we explored the effects of myriocin alone and in combination with cisplatin on tumor growth and vascular normalization in mouse models.

Results

We found that myriocin inhibited tumor growth and lung metastasis in mouse allograft tumor models. Myriocin induced normalization of the tumor vasculature in the mouse models. We also found that myriocin suppressed angiogenesis through the VEGFR2/PI3K/AKT pathway in endothelial cells (ECs), as well as cancer cell migration by blocking the IκBα/NF-κB(p65)/MMP-9 pathway. Finally, we found that myriocin enhanced the drug delivery efficacy of cisplatin by increasing the integrity of tumor vasculature in the mouse models, which synergistically increased the anti-tumor activity of cisplatin.

Conclusion

We suggest that myriocin is a novel potent anti-cancer agent that dually targets both VEGFR2 in ECs and IκBα in cancer cells, and exerts more pronounced anti-tumor effects than with either kinase being inhibited alone.

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Data Availability

The data used to support the findings of this study are included within the article.

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Funding

This research was supported by National Research Foundation (NRF) grants funded by the Korean government (MSIP) (2017R1A2B3002227 & 2020R1A5A2017323).

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Authors and Affiliations

  1. Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, 80 Daehakro, Bukgu, Daegu, 41566, Republic of Korea

    Ji-Hak Jeong, Uttam Ojha, Hyeonha Jang, Sunhee Lee & You Mie Lee

  2. National Basic Research Lab. of Vascular Homeostasis Regulation, College of Pharmacy, Kyungpook National University, 80 Daehakro, Bukgu, Daegu, 41566, Republic of Korea

    Ji-Hak Jeong, Uttam Ojha, Hyeonha Jang, Soohyun Kang & You Mie Lee

  3. College of Pharmacy, Kyungpook National University, 80 Daehakro, Bukgu, Daegu, 41566, Republic of Korea

    Ji-Hak Jeong, Uttam Ojha, Hyeonha Jang, Soohyun Kang, Sunhee Lee & You Mie Lee

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  1. Ji-Hak Jeong
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  2. Uttam Ojha
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Contributions

YML directed this project. J-HJ, HJ, SK, and SL designed in vitro and in vivo experiments. J-HJ, UO, HJ, SK, and SL performed the experiments and data analysis. J-HJ, HJ and YML interpreted the data. J-HJ and YML wrote the manuscript.

Corresponding author

Correspondence to You Mie Lee.

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All the animal experiments in the study were conducted according to the Guidelines for Care and Use of Laboratory Animals issued by the Institutional Ethical Animal Care Committee of Kyungpook National University (Protocol number: KNU 2014–0189 and KNU 2017–0145). No any human participants were involved.

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Jeong, JH., Ojha, U., Jang, H. et al. Dual anti-angiogenic and anti-metastatic activity of myriocin synergistically enhances the anti-tumor activity of cisplatin. Cell Oncol. 46, 117–132 (2023). https://doi.org/10.1007/s13402-022-00737-x

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