Yoshiyuki Kawamoto, Yui Furuhashi, Silvi Zakiyatul Ilmiyah, Seiji Yamaguchi, Nozomi Nishimura, Riko Iwata, Arisa Imoto, Takashi Murate, Yuhsuke Ohmi, Sofy Permana, Agustina Tri Endharti, Yuki Ueno, Machiko Iida, Ichiro Yajima, Nobutaka Ohgami, Masashi Kato, Kozue Takeda
Despite extensive development of anticancer agents, there remains a critical need for therapeutics with novel mechanisms of action. This study reports the potent anticancer activity and mechanistic analysis of highly water-soluble dopa-melanin (DM) prepared through a unique synthetic process. DM exhibits distinctive structural and chemical properties that contribute to its exceptional aqueous solubility (≥50 mg/ml) and may underlie its enhanced biological activity. DM reduced cell viability in multiple cancer cell lines. Using HeLa cells as a representative model, DM suppressed cell migration and three-dimensional growth. Fractionation revealed that activity was associated with polymers larger than 30 kDa, suggesting a critical role for high-molecular-weight species. Mechanistic studies showed that DM induced S/G2/M arrest followed by cell death with minimal apoptotic body formation. DM rapidly decreased cyclin D1 and D3 protein and mRNA levels. A pan-caspase inhibitor significantly suppressed DM's inhibitory effect on cell viability but did not prevent cyclin D degradation. Cyclin D degradation was mediated through calcium-dependent calpain activation triggered by endoplasmic reticulum Ca2+ release via IP3 receptors, and inhibition of this pathway attenuated DM's activity. In a mouse syngeneic tumor model, oral administration of DM significantly inhibited tumor growth without apparent toxicity. These results demonstrate that both caspase-dependent apoptosis and a caspase-independent cyclin D degradation pathway contribute to DM-induced cell death. Its high solubility, oral efficacy, and unique mechanism of action make DM a promising candidate for therapeutic development. © 2026 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi, Kasugai, Japan; Doctoral Program in Medical Sciences, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia; Department of Clinical Engineering, College of Life and Health Sciences, Chubu University, Aichi, Kasugai, Japan; Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Brawijaya, Malang, Indonesia; Department of Clinical Parasitology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia; Department of Health and Nutritional Sciences, Faculty of Health Sciences, Aichi Gakuin University, Aichi, Nisshin, Japan; Department of Disease Model, Institute For Developmental Research, Aichi Developmental Disability Center, Aichi, Kasugai, Japan; Unit of Molecular and Cellular Toxicology, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, Saitama, Japan; Department of Hygiene, Fujita Heath University School of Medicine, Aichi, Toyoake, Japan; Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Aichi, Nagoya, Japan
