Tetra-O-methyl nordihydroguaiaretic acid induces G₂ arrest in mammalian cells and exhibits tumoricidal activity in vivo

The transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M₄N) was found to arrest the proliferation of C3, C33a, CEM-T4, and TC-1 cells in culture at the G₂ stage of the cell cycle. Investigation into the mechanism of arrest revealed that M₄N reduces mRNA levels and subsequent protein production of the cyclin-dependent kinase CDC2, resulting in the inactivation of the CDC2/cyclin B complex (maturation promoting factor). When injected intratumorally in a C3-cell induced C57b1/6 mouse tumor model system, M₄N demonstrated substantial tumoricidal activity that correlated with a reduction in tumor cell CDC2 protein levels. These findings suggest that M₄N may be a useful chemotherapeutic agent for the control of unregulated cellular proliferation.