{
  "abstract": "Colorectal cancer (CRC) remains a major cause of cancer mortality, motivating strategies targeting noncanonical tumor vulnerabilities. Public gene-expression datasets identified ion channel–associated genes upregulated in primary CRC and COLO 205 cells versus normal colon, guiding a screen of 17 ion-modulating compounds. Nine inhibited COLO 205 proliferation. Leading compounds suppressed COLO 205, HT-29, and Caco-2 growth, predominantly inducing cytostasis with G1/G0 accumulation. Most were less active in 3D COLO 205 spheroids than 2D monolayers; only compounds blocking both potassium and calcium channels reduced spheroid size. However, our lead compound, clofilium retained 3D activity, reducing COLO 205 and HT-29 spheroid size, cohesion, migration, and invasion, plus COLO 205 intravasation and endothelial sprouting in heterotypic tumor–stroma spheroids. Across leading compounds, cytostasis frequently coincided with prolonged depolarization and reduced cytoplasmic Ca2+. Clofilium induced sustained depolarization, growth suppression after withdrawal, senescence-associated features, and altered mitochondrial membrane potential and content. RNA sequencing of clofilium-treated COLO 205 cells revealed suppressed DNA-replication, cell-cycle, chromatin-maintenance, CRC-stemness programs, and induced ER-stress, cell-cycle-inhibitory, metabolic-adaptation, innate immune, and ion-homeostasis pathways. Protein analyses in COLO 205 and HT-29 cells showed increased NDRG1, p21, IRE1α, and CHOP, with cell-line-specific kinase-signaling changes. In COLO 205 xenografts, daily intravenous clofilium reduced mean tumor-volume change from baseline by 43% versus vehicle controls, with limited observable systemic toxicity. These findings implicate CRC ion-transport networks and bioelectric states as therapeutic vulnerabilities. Clofilium emerged as a lead ionoceutical candidate with activity across 2D, 3D, heterotypic microenvironment, and xenograft models, supporting further evaluation of multi-channel ion-modulating strategies for CRC.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Juanita Mathews"
    },
    {
      "name": "Sydney A. Palmer"
    },
    {
      "name": "Sammy Hansali"
    },
    {
      "name": "Jordan Strasser"
    },
    {
      "name": "Alyssa Liao"
    },
    {
      "name": "Gayathri Kondakath"
    },
    {
      "name": "Zoe Mozden Weiner"
    },
    {
      "name": "Léo Pio-Lopez"
    },
    {
      "name": "Franz Kuchling"
    },
    {
      "name": "Eva Swei"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e46nqrmfvaw77.bib",
  "cited_by": 0,
  "doi": "10.31219/osf.io/w5dq7_v4",
  "fulltext_url": null,
  "id": "e46nqrmfvaw77",
  "issns": [],
  "landing_url": "https://osf.io/w5dq7_v4/",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "bepress",
      "Cell and Developmental Biology"
    ],
    [
      "bepress",
      "Chemicals and Drugs"
    ],
    [
      "bepress",
      "Life Sciences"
    ],
    [
      "bepress",
      "Medical Sciences"
    ],
    [
      "bepress",
      "Medicine and Health Sciences"
    ],
    [
      "bepress",
      "Pharmacy and Pharmaceutical Sciences"
    ],
    [
      "bepress",
      "Physiology"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7222964238",
  "pdf_url": "https://osf.io/w5dq7/download",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-19",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e46nqrmfvaw77.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:57Z",
      "native_id": "w5dq7",
      "source": "osf",
      "url": "https://osf.io/w5dq7_v4/"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "bepress:Life Sciences",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "bepress:Physiology",
      "subfield": "physiology"
    }
  ],
  "title": "Targeting Ion Channel Dysregulation in Colorectal Cancer: Identification of Clofilium as a Potent Inhibitor of Tumor Growth and Metastatic Potential",
  "title_text": "Targeting Ion Channel Dysregulation in Colorectal Cancer: Identification of Clofilium as a Potent Inhibitor of Tumor Growth and Metastatic Potential",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:57Z",
  "url": "https://research.draconitic.com/paper/e46nqrmfvaw77",
  "venue": "OSF Preprints",
  "versions": []
}