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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1520881
This article is part of the Research Topic The Role of Tumor Microenvironment in Malignant Progression and Target Validation View all 3 articles

Exploring the Anti-Metastatic Potential of Sunitinib and Novel Analogs in Colorectal Cancer: Insights into HIF-1α Mediated Metastasis

Provisionally accepted
Fatemeh B. Rassouli Fatemeh B. Rassouli 1*Maryam Moghadam Matin Maryam Moghadam Matin 2Farzin Hadizade Farzin Hadizade 3Masoud Nejabat Masoud Nejabat 2Hossein Allaverdizade Hossein Allaverdizade 2Shahin Gharedaghi Shahin Gharedaghi 4Halime Hassanze Halime Hassanze 2
  • 1 Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
  • 2 Ferdowsi University of Mashhad, Mashhad, Iran
  • 3 Mashhad University of Medical Sciences, Mashhad, Razavi Khorasan, Iran
  • 4 Hamadan University of Medical Sciences, Hamedan, Hamadan, Iran

The final, formatted version of the article will be published soon.

    Colorectal cancer (CRC) is a prevalent malignancy worldwide with high mortality rate. Metastasis, the primary cause of cancer-related deaths, is attributed to various factors including tumor hypoxia. Due to the urgent demand for potent anti-metastatic agents, we aimed to determine the effects of sunitinib and novel analogs on the metastatic behavior of human CRC cells in hypoxic condition for the first time. For in silico analyses, pathogenic targets of metastatic CRC were identified, PPI network was constructed and KEGG pathway enrichment analysis was conducted. The expression of HIF1A was evaluated in seven CRC cell lines, and computational modeling was carried out to define the interaction of sunitinib with HIF-1α. For in vitro studies, analogs of sunitinib were synthesized, and cells were assessed for viability, migration, invasion, MMPs activity and gene expression in hypoxic condition. Computational analyses highlighted the importance of HIF-1α as a crucial mediator of metastasis in CRC. Molecular docking and dynamics simulations demonstrated favorable and stable interaction of sunitinib and three novel analogs with HIF-1α PAS-B domain. Volcano plots indicated upregulation of HIF1A in LoVo cells compared to six other CRC cell lines. Findings of in vitro studies revealed considerable inhibitory effects of sunitinib and analogs on LoVo cell migration and invasion in hypoxic condition. Gelatin zymography and qPCR analysis indicated decreased activity of MMP-2 and MMP-9, along with downregulation of EMT transcription factors in hypoxic condition. Current study reports promising anti-metastatic effects of sunitinib and novel analogs on CRC cells, providing foundation for further investigation to combat cancer metastasis.

    Keywords: Colon Cancer, metastasis, Sunitinib, Novel analogs, hypoxia

    Received: 31 Oct 2024; Accepted: 10 Jan 2025.

    Copyright: © 2025 Rassouli, Matin, Hadizade, Nejabat, Allaverdizade, Gharedaghi and Hassanze. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Fatemeh B. Rassouli, Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran

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