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Source: Molecular Cancer Therapeutics
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Total 96 results found since Jan 2013.
Mutant BRAF Upregulates MCL-1 to Confer Apoptosis Resistance that Is Reversed by MCL-1 Antagonism and Cobimetinib in Colorectal Cancer
Oncogenic BRAFV600E mutations activate MAPK signaling and are associated with treatment resistance and poor prognosis in patients with colorectal cancer. In BRAFV600E-mutant colorectal cancers, treatment failure may be related to BRAFV600E-mediated apoptosis resistance that occurs by an as yet undefined mechanism. We found that BRAFV600E can upregulate anti-apoptotic MCL-1 in a gene dose-dependent manner using colorectal cancer cell lines isogenic for BRAF. BRAFV600E-induced MCL-1 upregulation was confirmed by ectopic BRAFV600E expression that activated MEK/ERK signaling to phosphorylate (MCL-1Thr163) and stabilize MCL-1. ...
Source: Molecular Cancer Therapeutics - November 30, 2016 Category: Cancer & Oncology Authors: Kawakami, H., Huang, S., Pal, K., Dutta, S. K., Mukhopadhyay, D., Sinicrope, F. A. Tags: Cancer Biology and Signal Transduction Source Type: research
A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells
The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Toriyama, S., Horinaka, M., Yasuda, S., Taniguchi, T., Aono, Y., Takamura, T., Morioka, Y., Miki, T., Ukimura, O., Sakai, T. Tags: Small Molecule Therapeutics Source Type: research
Vitamin D Enhances the Efficacy of Irinotecan through miR-627-Mediated Inhibition of Intratumoral Drug Metabolism
Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D–regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer ce...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Sun, M., Zhang, Q., Yang, X., Qian, S. Y., Guo, B. Tags: Small Molecule Therapeutics Source Type: research
Direct Pharmacological Inhibition of {beta}-Catenin by RNA Interference in Tumors of Diverse Origin
In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Signif...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., Siddiquee, Z., Craig, K., Lai, C., Dudek, H., Monga, S. P., Wang, W., Brown, B. D., Abrams, M. T. Tags: Large Molecule Therapeutics Source Type: research
HDACi and Celecoxib Induce Apoptosis in Bladder Cancer
The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Toriyama, S., Horinaka, M., Yasuda, S., Taniguchi, T., Aono, Y., Takamura, T., Morioka, Y., Miki, T., Ukimura, O., Sakai, T. Tags: Small Molecule Therapeutics Source Type: research
Vitamin D Inhibits Intratumoral Drug Metabolism
Cytochrome P450 enzyme CYP3A4 is an important drug-metabolizing enzyme, and high levels of tumoral expression of CYP3A4 are linked to drug resistance. We investigated the function of vitamin D–regulated miR-627 in intratumoral CYP3A4 suppression and its role in enhancing the efficacy of chemotherapy. We found that miR-627 targets CYP3A4 and suppresses CYP3A4 expression in colon cancer cell lines. Furthermore, calcitriol (the active form of vitamin D) suppressed CYP3A4 expression by activating miR-627. As a result, calcitriol inhibited CYP3A4-mediated metabolism of irinotecan (a topoisomerase I inhibitor) in cancer ce...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Sun, M., Zhang, Q., Yang, X., Qian, S. Y., Guo, B. Tags: Small Molecule Therapeutics Source Type: research
{beta}-Catenin Targeting DsiRNAs
In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDX) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, and murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Signif...
Source: Molecular Cancer Therapeutics - August 31, 2016 Category: Cancer & Oncology Authors: Ganesh, S., Koser, M. L., Cyr, W. A., Chopda, G. R., Tao, J., Shui, X., Ying, B., Chen, D., Pandya, P., Chipumuro, E., Siddiquee, Z., Craig, K., Lai, C., Dudek, H., Monga, S. P., Wang, W., Brown, B. D., Abrams, M. T. Tags: Large Molecule Therapeutics Source Type: research
Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule in...
Source: Molecular Cancer Therapeutics - August 2, 2016 Category: Cancer & Oncology Authors: Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., Ruggieri, R. Tags: Small Molecule Therapeutics Source Type: research
Radiosensitization of Medulloblastoma by Inhibition of MRK
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule in...
Source: Molecular Cancer Therapeutics - August 2, 2016 Category: Cancer & Oncology Authors: Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., Ruggieri, R. Tags: Small Molecule Therapeutics Source Type: research
Dasatinib/ARID1A Synthetic Lethality in OCCC
New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to ...
Source: Molecular Cancer Therapeutics - July 4, 2016 Category: Cancer & Oncology Authors: Miller, R. E., Brough, R., Bajrami, I., Williamson, C. T., McDade, S., Campbell, J., Kigozi, A., Rafiq, R., Pemberton, H., Natrajan, R., Joel, J., Astley, H., Mahoney, C., Moore, J. D., Torrance, C., Gordan, J. D., Webber, J. T., Levin, R. S., Shokat, K. Tags: Small Molecule Therapeutics Source Type: research
Cyclin-Dependent Kinase 11 and Ovarian Cancer
Ovarian cancer is currently the most lethal gynecologic malignancy with limited treatment options. Improved targeted therapies are needed to combat ovarian cancer. Here, we report the identification of cyclin-dependent kinase 11 (CDK11) as a mediator of tumor cell growth and proliferation in ovarian cancer cells. Although CDK11 has not been implicated previously in this disease, we have found that its expression is upregulated in human ovarian cancer tissues and associated with malignant progression. Metastatic and recurrent tumors have significantly higher CDK11 expression when compared with the matched, original primary ...
Source: Molecular Cancer Therapeutics - July 4, 2016 Category: Cancer & Oncology Authors: Liu, X., Gao, Y., Shen, J., Yang, W., Choy, E., Mankin, H., Hornicek, F. J., Duan, Z. Tags: Cancer Biology and Signal Transduction Source Type: research
Genome and Immune Profiling of Inflammatory Breast Cancer
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted next-generation sequencing (NGS) and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biologic pathways, including ac...
Source: Molecular Cancer Therapeutics - July 4, 2016 Category: Cancer & Oncology Authors: Hamm, C. A., Moran, D., Rao, K., Trusk, P. B., Pry, K., Sausen, M., Jones, S., Velculescu, V. E., Cristofanilli, M., Bacus, S. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Edelfosine for Prostate Cancer
Edelfosine is a synthetic alkyl-lysophospholipid that possesses significant antitumor activity in several human tumor models. Here, we investigated the effects of edelfosine combined with androgen deprivation (AD) in LNCaP and VCaP human prostate cancer cells. This treatment regimen greatly decreased cell proliferation compared with single agent or AD alone, resulting in higher levels of apoptosis in LNCaP compared with VCaP cells. Edelfosine caused a dose-dependent decrease in AKT activity, but did not affect the expression of total AKT in either cell line. Furthermore, edelfosine treatment inhibited the expression of and...
Source: Molecular Cancer Therapeutics - June 1, 2016 Category: Cancer & Oncology Authors: Udayakumar, T. S., Stoyanova, R., Shareef, M. M., Mu, Z., Philip, S., Burnstein, K. L., Pollack, A. Tags: Cancer Biology and Signal Transduction Source Type: research
Kpn{beta}1 as an Anticancer Target
This study aimed to identify novel small molecule inhibitors of Kpnβ1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnβ1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl)pyrrolo[5,4-b]quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpnβ1 and known Kpnβ1 cargoes NFAT, NFB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of IN...
Source: Molecular Cancer Therapeutics - April 4, 2016 Category: Cancer & Oncology Authors: van der Watt, P. J., Chi, A., Stelma, T., Stowell, C., Strydom, E., Carden, S., Angus, L., Hadley, K., Lang, D., Wei, W., Birrer, M. J., Trent, J. O., Leaner, V. D. Tags: Small Molecule Therapeutics Source Type: research
HSP90 Inhibition Kills Mutant KRAS Colon Cancer Cells
Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolis...
Source: Molecular Cancer Therapeutics - March 6, 2016 Category: Cancer & Oncology Authors: Wang, C. Y., Guo, S. T., Wang, J. Y., Liu, F., Zhang, Y. Y., Yari, H., Yan, X. G., Jin, L., Zhang, X. D., Jiang, C. C. Tags: Cancer Biology and Signal Transduction Source Type: research
