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Full-Text Articles in Cancer Biology
Epigenetic Targeting Of Mcl-1 Is Synthetically Lethal With Bcl-Xl/Bcl-2 Inhibition In Model Systems Of Glioblastoma, Enyuan Shang, Trang T. T. Nguyen, Chang Shu, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Epigenetic Targeting Of Mcl-1 Is Synthetically Lethal With Bcl-Xl/Bcl-2 Inhibition In Model Systems Of Glioblastoma, Enyuan Shang, Trang T. T. Nguyen, Chang Shu, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Publications and Research
Apoptotic resistance remains a hallmark of glioblastoma (GBM), the most common primary brain tumor in adults, and a better understanding of this process may result in more efficient treatments. By utilizing chromatin immunoprecipitation with next-generation sequencing (CHIP-seq), we discovered that GBMs harbor a super enhancer around the Mcl-1 locus, a gene that has been known to confer cell death resistance in GBM.We utilized THZ1, a known super-enhancer blocker, and BH3-mimetics, including ABT263, WEHI-539, and ABT199. Combined treatment with BH3-mimetics and THZ1 led to synergistic growth reduction in GBM models. Reduction in cellular viability was accompanied by significant cell death induction …
Inhibition Of Hdac1/2 Along With Trap1 Causes Synthetic Lethality In Glioblastoma Model Systems, Trang T. T. Nguyen, Yiru Zhang, Enyuan Shang, Chang Shu, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Inhibition Of Hdac1/2 Along With Trap1 Causes Synthetic Lethality In Glioblastoma Model Systems, Trang T. T. Nguyen, Yiru Zhang, Enyuan Shang, Chang Shu, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
Publications and Research
The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and …
Activation Of Lxrβ Inhibits Tumor Respiration And Is Synthetically Lethal With Bcl-Xl Inhibition, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Consuelo Torrini, Yiru Zhang, Elena Bianchetti, Maria J. Sanchez-Quintero, Giulio Kleiner, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin
Activation Of Lxrβ Inhibits Tumor Respiration And Is Synthetically Lethal With Bcl-Xl Inhibition, Trang Thi Thu Nguyen, Chiaki Tsuge Ishida, Enyuan Shang, Chang Shu, Consuelo Torrini, Yiru Zhang, Elena Bianchetti, Maria J. Sanchez-Quintero, Giulio Kleiner, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin
Publications and Research
Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-13C-glucose and U-13C-glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading …
Toward Repurposing Metformin As A Precision Anti-Cancer Therapy Using Structural Systems Pharmacology, Thomas Hart, Shihab Dider, Weiwei Han, Hua Xu, Zhongming Zhao, Lei Xie
Toward Repurposing Metformin As A Precision Anti-Cancer Therapy Using Structural Systems Pharmacology, Thomas Hart, Shihab Dider, Weiwei Han, Hua Xu, Zhongming Zhao, Lei Xie
Publications and Research
Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally …