Metformin Synergizes with BCL-XL/BCL-2 Inhibitor ABT-263 to Induce Apoptosis Specifically in p53-Defective Cancer Cells
In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the proapoptotic machineries in various p53-defective cancer cells. Mechanistic studies revealed that metformin sensitized ABT-263 via attenuating mTORC1-mediated cap-dependent translation of MCL-1 and survivin and weakening internal ribosome entry site (IRES)-dependent translation of XIAP. Meanwhile, ABT-263 sensitized metformin through disrupting the BCL-XL/BIM complex. However, metformin and ABT-263 had no synergistic killing effect in p53 wild-type (p53-WT) cancer cells becaus...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Li, X., Li, B., Ni, Z., Zhou, P., Wang, B., He, J., Xiong, H., Yang, F., Wu, Y., Lyu, X., Zhang, Y., Zeng, Y., Lian, J., He, F. Tags: Small Molecule Therapeutics Source Type: research
Discovery of a Novel Small-Molecule Inhibitor that Targets PP2A-{beta}-Catenin Signaling and Restricts Tumor Growth and Metastasis
Molecular hybridization of different pharmacophores to tackle both tumor growth and metastasis by a single molecular entity can be very effective and unique if the hybrid product shows drug-like properties. Here, we report synthesis and discovery of a novel small-molecule inhibitor of PP2A–β-catenin signaling that limits both in vivo tumor growth and metastasis. Our molecular hybridization approach resulted in cancer cell selectivity and improved drug-like properties of the molecule. Inhibiting PP2A and β-catenin interaction by selectively engaging PR55α-binding site, our most potent small-molecule in...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Maheshwari, S., Avula, S. R., Singh, A., Singh, L. R., Palnati, G. R., Arya, R. K., Cheruvu, S. H., Shahi, S., Sharma, T., Meena, S., Singh, A. K., Kant, R., Riyazuddin, M., Bora, H. K., Siddiqi, M. I., Gayen, J. R., Sashidhara, K. V., Datta, D. Tags: Small Molecule Therapeutics Source Type: research
Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma
In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Giulino-Roth, L., van Besien, H. J., Dalton, T., Totonchy, J. E., Rodina, A., Taldone, T., Bolaender, A., Erdjument-Bromage, H., Sadek, J., Chadburn, A., Barth, M. J., Dela Cruz, F. S., Rainey, A., Kung, A. L., Chiosis, G., Cesarman, E. Tags: Small Molecule Therapeutics Source Type: research
{beta}-Catenin Inhibitor BC2059 Is Efficacious as Monotherapy or in Combination with Proteasome Inhibitor Bortezomib in Multiple Myeloma
Currently available treatment options are unlikely to be curative for the majority of multiple myeloma patients, emphasizing a continuing role for the introduction of investigational agents that can overcome drug resistance. The canonical Wnt/β-catenin signaling pathway, essential for self-renewal, growth, and survival, has been found to be dysregulated in multiple myeloma, particularly in advanced stages of disease. This provides the rationale for evaluating the novel β-catenin inhibitor BC2059 as monotherapy and in combination with proteasome inhibitors in vitro and in vivo. Here, we show nuclear localization o...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Savvidou, I., Khong, T., Cuddihy, A., McLean, C., Horrigan, S., Spencer, A. Tags: Small Molecule Therapeutics Source Type: research
CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5 cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic comb...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Francis, A. M., Alexander, A., Liu, Y., Vijayaraghavan, S., Low, K. H., Yang, D., Bui, T., Somaiah, N., Ravi, V., Keyomarsi, K., Hunt, K. K. Tags: Small Molecule Therapeutics Source Type: research
Preclinical Efficacy and Molecular Mechanism of Targeting CDK7-Dependent Transcriptional Addiction in Ovarian Cancer
Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identi...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Zhang, Z., Peng, H., Wang, X., Yin, X., Ma, P., Jing, Y., Cai, M.-C., Liu, J., Zhang, M., Zhang, S., Shi, K., Gao, W.-Q., Di, W., Zhuang, G. Tags: Small Molecule Therapeutics Source Type: research
Cotargeting of MEK and PDGFR/STAT3 Pathways to Treat Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments. Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a two-dimensional monolayer culture system as well as three-dimensional spheroid culture system, we conducted a screen of a large panel of anticancer agents and found ...
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Authors: Sahu, N., Chan, E., Chu, F., Pham, T., Koeppen, H., Forrest, W., Merchant, M., Settleman, J. Tags: Small Molecule Therapeutics Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - September 4, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Correction: Dedifferentiation of Glioma Cells to Glioma Stem-like Cells By Therapeutic Stress-induced HIF Signaling in the Recurrent GBM Model
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Tags: Correction Source Type: research
PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells
Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP2...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Cai, W., Chen, G., Luo, Q., Liu, J., Guo, X., Zhang, T., Ma, F., Yuan, L., Li, B., Cai, J. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Biological Role and Therapeutic Targeting of TGF-{beta}3 in Glioblastoma
Transforming growth factor (TGF)-β contributes to the malignant phenotype of glioblastoma by promoting invasiveness and angiogenesis and creating an immunosuppressive microenvironment. So far, TGF-β1 and TGF-β2 isoforms have been considered to act in a similar fashion without isoform-specific function in glioblastoma. A pathogenic role for TGF-β3 in glioblastoma has not been defined yet. Here, we studied the expression and functional role of endogenous and exogenous TGF-β3 in glioblastoma models. TGF-β3 mRNA is expressed in human and murine long-term glioma cell lines as well as in human gliom...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Seystahl, K., Papachristodoulou, A., Burghardt, I., Schneider, H., Hasenbach, K., Janicot, M., Roth, P., Weller, M. Tags: Cancer Biology and Signal Transduction Source Type: research
Disruption of TCF/{beta}-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells
In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces in vitro antitumor activity in a panel of prevalent representative STS cell lines and primary cultures. At the molecular level, PKF118-310 treatment reduced β-catenin nuclear localization, reporter activity, and target genes, resulting in an increase in apoptosis. Importantly, combination of PKF118-...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Martinez-Font, E., Felipe-Abrio, I., Calabuig-Farinas, S., Ramos, R., Terrasa, J., Vögler, O., Alemany, R., Martin-Broto, J., Obrador-Hevia, A. Tags: Cancer Biology and Signal Transduction Source Type: research
Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma
This study suggests that Tβ4 expression triggered by epigenetic alterations could contribute to the development of resistance to antiangiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in hepatocellular carcinoma. Mol Cancer Ther; 16(6); 1155–65. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Ohata, Y., Shimada, S., Akiyama, Y., Mogushi, K., Nakao, K., Matsumura, S., Aihara, A., Mitsunori, Y., Ban, D., Ochiai, T., Kudo, A., Arii, S., Tanabe, M., Tanaka, S. Tags: Cancer Biology and Signal Transduction Source Type: research
Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SN...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Jin, M. H., Nam, A.-R., Park, J. E., Bang, J.-H., Bang, Y.-J., Oh, D.-Y. Tags: Cancer Biology and Signal Transduction Source Type: research
Focal Adhesion Kinase as a Potential Target in AML and MDS
Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P = 2 x 10–4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P = 0.0024) ...
Source: Molecular Cancer Therapeutics - June 1, 2017 Category: Cancer & Oncology Authors: Carter, B. Z., Mak, P. Y., Wang, X., Yang, H., Garcia-Manero, G., Mak, D. H., Mu, H., Ruvolo, V. R., Qiu, Y., Coombes, K., Zhang, N., Ragon, B., Weaver, D. T., Pachter, J. A., Kornblau, S., Andreeff, M. Tags: Cancer Biology and Signal Transduction Source Type: research
