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

Abstract

<jats:title>Abstract</jats:title> <jats:p>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 documented previously 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 &amp;lt; 0.01), compared with the controls. Moreover, MDC-1112 extended survival in an intracranial xenograft model. Although all vehicle-treated mice died by 19 days of treatment, 7 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.</jats:p> <jats:p>New therapeutic options are needed for glioblastoma. The novel agent MDC-1112 is an effective anticancer agent in multiple animal models of glioblastoma, and its mechanism of action involves the inhibition of STAT3 phosphorylation, primarily at its Serine 727 residue.</jats:p>

STAT3 and STAT5 Activation in Solid Cancers

“…In addition to their canonical roles in inflammation and immunity, STAT3 and STAT5 have been shown to localize to mitochondria. The mitochondrial localization of STAT3 is required for its ability to support malignant transformation in murine embryonic fibroblasts and breast cancer cells [43,44,45,46], and mito-STAT3 regulates mitochondrial metabolism and mitochondrial gene expression [45,47,48,49,50,51]. Several reports have suggested that STAT3 can be imported to mitochondria after phosphorylation on S727 [44,45] or upon acetylation [52,53].…”

From HDAC to Voltage-Gated Ion Channels: What’s Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer

“…In vivo, MDC-1112 reduced the growth of subcutaneous GBM xenografts in mice by up to 78.2% vs. controls. Moreover, MDC-1112 extended survival in an intracranial xenograft model [ 219 ].…”

Exploiting the Complexities of Glioblastoma Stem Cells: Insights for Cancer Initiation and Therapeutic Targeting

“…In vivo, this new STAT3 inhibitor impaired glioma growth [179]. The use of MDC-1112, which was demonstrated to inhibit STAT3 phosphorylation at the serine 727, significantly inhibited the growth of GBM cell lines and their clonogenicity in vitro [180]. In vivo, it was associated with decreased tumor volume and increased mouse survival [180].…”

“…The use of MDC-1112, which was demonstrated to inhibit STAT3 phosphorylation at the serine 727, significantly inhibited the growth of GBM cell lines and their clonogenicity in vitro [180]. In vivo, it was associated with decreased tumor volume and increased mouse survival [180]. WP1066, which is now in a Phase I clinical trial recruiting patients with recurrent malignant gliomas (NCT01904123), showed promising preclinical results [181].…”