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Carcinogenesis. 2019 Apr 17. pii: bgz069. doi: 10.1093/carcin/bgz069. [Epub ahead of print]

Phospho-valproic acid (MDC-1112) suppresses glioblastoma growth in preclinical models through the inhibition of STAT3 phosphorylation.

Author information

1
Department of Nutrition, University of California, Davis. One Shields Ave, Davis, CA, USA.
2
Department of Thyroid Surgery, Sun Yat-Sen University, Guangzhou, China.
3
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
4
Department of Family, Population and Preventive Medicine, Stony Brook, NY, USA.
5
Department of Medicine, Stony Brook, NY, USA.
6
Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.

Abstract

New therapeutic strategies against glioblastoma multiforme (GBM) are urgently needed. Signal transducer and activator of transcription 3 (STAT3), constitutively active in many GBM tumors, plays a major role in GBM tumor growth and represents a potential therapeutic target. We have previously documented that phospho-valproic acid (MDC-1112), which inhibits STAT3 activation, possesses strong anticancer properties in multiple cancer types. In this study, we explored the anticancer efficacy of MDC-1112 in preclinical models of GBM, and evaluated its mode of action. MDC-1112 inhibited the growth of multiple human GBM cell lines in a concentration- and time-dependent manner. Normal human astrocytes were resistant to MDC-1112, indicating selectivity. In vivo, MDC-1112 reduced the growth of subcutaneous GBM xenografts in mice by up to 78.2% (p<0.01), compared to the controls. Moreover, MDC-1112 extended survival in an intracranial xenograft model. While all vehicle-treated mice died by 19 days of treatment, 7 out of 11 MDC-1112-treated mice were alive and healthy by the end of 5 weeks, with many showing tumor regression. Mechanistically, MDC-1112 inhibited STAT3 phosphorylation at the serine 727 residue, but not at tyrosine 705, in vitro and in vivo. STAT3 overexpression rescued GBM cells from the cell growth inhibition by MDC-1112. In addition, MDC-1112 reduced STAT3 levels in the mitochondria and enhanced mitochondrial levels of reactive oxygen species, which triggered apoptosis. In conclusion, MDC-1112 displays strong efficacy in preclinical models of GBM, with the serine 727 residue of STAT3 being its key molecular target. MDC-1112 merits further evaluation as a drug candidate for GBM.

PMID:
30994173
DOI:
10.1093/carcin/bgz069

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