Natural bioactive compounds for cancer cell proliferation suppression Cancer growth suppression targeting nucleotide metabolism and DNA repair systems

We provide natural products containing cancer growth suppression activities selected from biologically active microbial metabolites that were discovered and isolated at the Institute of Microbial Chemistry (BIKAKEN). Cancer cells exhibit exceptionally high rates of proliferation and require a massive supply of nucleotides, such as GTP, to support DNA and RNA replication, as well as protein synthesis (ribosome biogenesis). Recent findings demonstrate that the genetic or pharmacological inhibition of IMPDH1/2 and GMPS leads to the depletion of the GTP pool, resulting in significant suppression of cell proliferation across a wide range of cancer types.

* SDF (Structure Data Format) files of the compounds are available.
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* The products shown on this webpage are for research use only.

Inhibition of the GMP biosynthetic pathway leads to intracellular GTP depletion, which subsequently halts RNA transcription and ribosome biogenesis. In murine models, the disruption of this GTP supply has been shown to effectively suppress cancer cell proliferation and prolong survival.
Furthermore, thymidylate synthase (TS) in pyrimidine metabolism serves as the sole enzyme responsible for the conversion of dUMP to dTMP (thymidylic acid), a process essential for the supply of dTTP required for DNA synthesis. Pharmacological inhibition of this enzyme causes dTTP depletion, directly arresting DNA replication in cancer cells. Moreover, this dTTP deficiency inhibits the repair of DNA damage induced by radiation or chemotherapy, potentially offering a synergistic effect that further promotes cancer cell apoptosis.

Enzymes involved in DNA replication—the fundamental process of cell proliferation—are also attracting attention as promising therapeutic targets. DNA helicases function as enzymes that utilize ATP to unwind the DNA double helix, thereby facilitating the processes of replication, transcription, and repair. Inhibition of these functions triggers the following intracellular events:

• Abrogation of DNA Repair: The inability to unwind DNA, which is essential for recognizing and repairing damage sites, leads to the accumulation of severe lesions, such as DNA double-strand breaks (DSBs).
• Exacerbation of Replication Stress: The stalling of replication fork progression rapidly increases genomic instability.
• Induction of Apoptosis: Cells unable to maintain normal DNA metabolism eventually cease proliferation and are driven toward apoptosis.