Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma.

Cancer-specific inhibitors that reflect the unique metabolic needs of cancer cells are rare. Here we describe Gboxin, a small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F0F1 ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxin in the mitochondrial matrix. Administration of a metabolically stable Gboxin analogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents.

The soft underbelly of tumor cells.

In a recent Cell paper, Kitambi and colleagues identify a small molecule (Vacquinol-1) that has beneficial effects on a glioblastoma multiforme mouse model by oral administration. In glioblastoma cells, Vacquinol-1 targets macropinocytosis, a cellular process that will not lead to cell death in normal cells.

Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors.

Neurofibromatosis type I (NF1) is an autosomal disorder that affects neural crest-derived tissues, leading to a wide spectrum of clinical presentations. Patients commonly present with plexiform neurofibromas, benign but debilitating growths that can transform into malignant peripheral nerve sheath tumors (MPNST), a main cause of mortality. Currently, surgery is the primary course of treatment for MPNST, but with the limitation that these tumors are highly invasive. Radiotherapy is another treatment option, but is undesirable because it can induce additional mutations. Patients with MPNST may also receive doxorubicin as therapy, but this DNA-intercalating agent has relatively low tumor specificity and limited efficacy. In this study, we exploited a robust genetically engineered mouse model of MPNST that recapitulates human NF1-associated MPNST to identify a novel small chemical compound that inhibits tumor cell growth. Compound 21 (Cpd21) inhibits growth of all available in vitro models of MPNST and human MPNST cell lines, while remaining nontoxic to normally dividing Schwann cells or mouse embryonic fibroblasts. We show that this compound delays the cell cycle and leads to cellular apoptosis. Moreover, Cpd21 can reduce MPNST burden in a mouse allograft model, underscoring the compound's potential as a novel chemotherapeutic agent.

Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling.

The c-myc protooncogene is a key regulator of cell proliferation whose expression is reduced in normal epithelial cells in response to the growth inhibitory cytokine TGF-beta. Smad4 mediates this inhibitory effect of TGF-beta by forming a complex with Smad3, E2F4/5, and p107 at the TGF-beta inhibitory element (TIE) element on the c-myc promoter. In contrast, cell proliferation and c-myc expression are increased in response to Wnt ligands; this effect is mediated through the lymphoid enhancer-binding factor 1/T cell-specific factor (LEF/TCF) family of transcription factors on the c-myc promoter LEF/TCF-binding elements (TBE1 and TBE2). We report that a peptide aptamer designed to inhibit the binding between Smad4 and LEF/TCF reduced c-myc expression and the growth rate of HepG2 cells. Further analysis demonstrated that, in the absence of TGF-beta, Smad4 was bound to the positive regulatory element TBE1 from the c-myc promoter and activated c-myc promoter activity. Smad4 binding to the positive TBE1 c-myc element was reduced by TGF-beta, consistent with Smad4's inhibitory role on c-myc expression in response to TGF-beta. Reduction of Smad4 levels by RNAi knockdown also reduced c-myc expression levels and sensitized hepatocytes to cell death by serum deprivation. Two tumor-derived mutant Smad4 proteins that fail to mediate TGF-beta responses were still competent to cooperate with LEF1 to activate the c-myc promoter. These results support a previously unreported TGF-beta-independent function for Smad4 in cooperating with LEF/TCF to activate c-myc expression.