naphthoquinones and navitoclax

To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Benzofurans; Carcinoma, Hepatocellular; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Naphthoquinones; Sulfonamides; Xenograft Model Antitumor Assays

Vascular endothelial growth factor (VEGF) signaling promotes angiogenesis by stimulating the migration and proliferation of endothelial cells. The aim of this study was to investigate the expression of Survivin and VEGF receptor 1/2/3 (VEGFR 1/2/3) in esophageal carcinoma tissues (ECTs), and to explore the therapy effect of the suppression of VEGFR2 signaling. Here, we found that VEGFR2 and Survivin had high expressions and a significant correlation (r = 0.874, P < 0.002) in ECTs. Further, we found that VEGFR2 signaling could activate the AKT1/MDM2/Survivin pathway. The inhibition of VEGFR2 signaling with the XL184 treatment downregulated the phosphorylation of AKT1 and MDM2, and then, increased the activation of Caspase 3/7, resulting in the reduction of cell viability and the apoptosis of HUVECs. Additionally, in the esophageal tumor model, the tumor growth was significantly suppressed by blocking Survivin and the suppression of tumor growth was more effective in the combined treatment by blocking Survivin and Bcl-xl/Bcl-2. Our data thus revealed that Survivin in the signal downstream of VEGFR2 played an important role in esophageal cancer cell survival and might be a potential candidate target for the combined therapy for esophageal cancer.

Topics: Aniline Compounds; Animals; bcl-X Protein; Caspase 3; Caspase 7; Cell Line, Tumor; Cell Proliferation; Cell Survival; Esophageal Neoplasms; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Mice, Inbred BALB C; Models, Biological; Naphthoquinones; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Sulfonamides; Survivin; Up-Regulation; Vascular Endothelial Growth Factor Receptor-2

The selective survival advantage of culture-adapted human embryonic stem cells (hESCs) is a serious safety concern for their clinical application. With a set of hESCs with various passage numbers, we observed that a subpopulation of hESCs at late passage numbers was highly resistant to various cell death stimuli, such as YM155, a survivin inhibitor. Transcriptome analysis from YM155-sensitive (YM155S) and YM155-resistant (YM155R) hESCs demonstrated that BCL2L1 was highly expressed in YM155R hESCs. By matching the gene signature of YM155R hESCs with the Cancer Therapeutics Response Portal dataset, BH3 mimetics were predicted to selectively ablate these cells. Indeed, short-course treatment with a sub-optimal dose of BH3 mimetics induced the spontaneous death of YM155R, but not YM155S hESCs by disrupting the mitochondrial membrane potential. YM155S hESCs remained pluripotent following BH3 mimetics treatment. Therefore, the use of BH3 mimetics is a promising strategy to specifically eliminate hESCs with a selective survival advantage.

Topics: Aniline Compounds; bcl-X Protein; Cell Count; Cells, Cultured; Human Embryonic Stem Cells; Humans; Imidazoles; Naphthoquinones; Peptide Fragments; Proto-Oncogene Proteins; Stress, Physiological; Sulfonamides

Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited.

Topics: Aged; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; bcl-X Protein; Cell Line, Tumor; Colorectal Neoplasms; Female; Humans; Imidazoles; Mice; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Sulfonamides; Xenograft Model Antitumor Assays

YM155, a small-molecule survivin suppressant, exhibits anti-tumor activities in vitro, in vivo and in clinical trials. However, the mechanism of YM155 action remains unclear. In this study, YM155 was administered to a panel of cell lines and the effects of YM155 on Bcl-2 family members were analyzed. Our results show that YM155 strikingly downregulates Mcl-1 in a broad spectrum of cancer cell lines and that the Mcl-1 modulation occurs at the transcriptional level, independently of survivin modulation or caspase activity. Furthermore, analysis of the contribution of Mcl-1 or survivin downregulation to YM155-induced cell death in vitro showed that knockdown of Mcl-1 sensitizes cells to YM155-induced cytotoxicity. Finally, our data demonstrate that downregulation of Mcl-1 by YM155 synergistically lowers the threshold of Bcl-2 family member inhibitor ABT-263-induced cell death. Our findings reveal a novel mechanism by which survivin-independent Mcl-1 suppression plays a critical role in YM155-mediated anti-tumor activities. YM155 treatment in combination with ABT-263 thus affords a new strategy for cancer treatment.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Cell Death; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Our study aims to study the therapeutic effects of a novel Bcl-2 inhibitor, ABT-263, on hepatocellular carcinoma (HCC) and to provide primary preclinical data for future clinical trial with ABT-263. In this study we showed that Bcl-xL and survivin were up-regulated in HCC cell lines and human liver cancer tissues. Clinic used ABT-263 single treatment had no apoptotic effects on HCC cells whereas higher doses of ABT-263 did. Interestingly, the combination treatment of ABT-263 with survivin inhibitor YM-155 could result in significant apoptosis in HCC cells. Survivin inhibition through gene silencing significantly enhanced ABT-263 to induce apoptosis in HCC cells. We found that low dose of ABT-263 single treatment resulted in ERK activation and survivin up-regulation, which might be involved in the resistance of HCC cells to ABT-263 since blockade of ERK activation sensitized ABT-263-induced apoptosis. Importantly, ABT-263 and YM-155 combination treatment had no apoptotic effects on normal human hepatocytes. Taken together, these data suggest the combination treatment of Bcl-2 inhibitor and survivin inhibition may have a great potential for liver cancer therapy.

Topics: Aniline Compounds; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Gene Silencing; Hepatocytes; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Naphthoquinones; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Survivin