Systemic Treatment with Tetra-O-Methyl Nordihydroguaiaretic Acid Suppresses the Growth of Human Xenograft Tumors

Abstract

Purpose: We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M 4 N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M 4 N can be given systemically and inhibit the growth of five different human xenograft tumors. Experimental Design: Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M 4 N given i.v. or i.p. in a Cremophor EL^based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M 4 N. Results: Systemic M 4 N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M 4 N with tumor growth inhibitions (T/C values) of V42%, whereas the fifth, HT-29, responded to a lesser extent (48.3%). Growth arrest and apoptosis in both the xenograft tumors and in the tumor cells grown in culture were accompanied by reductions in both Cdc2 and tumor-specific survivin gene expression. Pharmacokinetic analysis following oral and i.v. administration to ICR mice indicated an absolute bioavailability for oral M 4 N of f88%. Minimal drug-related toxicity was observed. Conclusion: These preclinical studies establish that when given systemically, M 4 N can safely and effectively inhibit the growth of human tumors in nude mice.Cancers of all types are characterized by defects in the control or regulation of the cell cycle which result in unrestrained and aberrant cell proliferation. The CDC2-cyclin B1 complex, or MPF, is well established as the universal and key regulator of the G 2 -M phase transition of the cell cycle (1), and recent clinical studies showing elevated CDC2 expression in breast and colorectal carcinomas and the independent and prognostic association of CDC2 expression with tumor metastases, underscore the importance of this key cell cycle regulator in tumor progression (2, 3). Consequently, Cdc2 gene expression and activity represent an attractive target for antitumor drug development whose strategy is to selectively attenuate or prevent uncontrolled cell proliferation. We were first to report that the transcription inhibitor, tetra-O-methyl nordihydroguaiaretic acid (M 4 N), is capable of arresting the proliferation of several transformed and tumor cell lines in culture and exhibits tumoricidal activity in a C3 cell-induced mouse tumor model system (4). M 4 N-mediated arrest occurred at the G 2 stage of the cell cycle which correlated with a reduction in Cdc2 RNA levels, protein levels, and enzymatic activity. Our report was immediately followed by another which showed tha...

Targeting survivin in cancer therapy: fulfilled promises and open questions

“…One of those that directly affect survivin expression, tetra-O-methyl nordihydroguaiaretic acid (M(4)N), was shown to suppress Sp1-dependent survivin gene transcription and activate the mitochondrial apoptotic pathway in transformed cells (109). Moreover, M(4)N suppressed the growth of human xenograft tumors following systemic treatment (110). However, considering that the compound is a global transcription inhibitor, both survivin-dependent and survivin-independent pathways are thought to be responsible for drug-induced cell death in tumors (111).…”

Tetra-O-methyl nordihydroguaiaretic acid inhibits growth and induces death of leukemia cells independent of Cdc2 and survivin

“…One of the derivatives, tetra-Omethyl nordihydroguaiaretic acid (M4N) was shown to be able to induce G2 cell cycle arrest and exhibit anti-tumor activities in vivo [33,34]. The compound is currently in clinical trials in solid tumors.…”

“…The compound is currently in clinical trials in solid tumors. Mechanistic studies demonstrated that M4N induced cell cycle block and its anti-tumor activity was mediated by inhibiting expression of Sp1-dependent Cdc2 and survivin genes [34,35]. Recently, hedamycin was identified to inhibit and DEC1 to upregulate survivin transcription using the same mechanisms [36,37].…”

Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

“…In our experiments, NDGA and M 4 N showed similar antiviral activities against WNV and ZIKV at concentrations near to those that can be detected in tissues and plasma of treated animals (39,40). However, our CC 50 values for each compound evidenced that M 4 N displayed a reduced toxicity in comparison to that of NDGA.…”