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International Journal of Molecular... Feb 2020Glucose levels inside solid tumors are low as compared with normal surrounding tissue, forcing tumor cells to reprogram their metabolism to adapt to such low glucose...
The Amuvatinib Derivative, N-(2H-1,3-Benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, Inhibits Mitochondria and Kills Tumor Cells under Glucose Starvation.
Glucose levels inside solid tumors are low as compared with normal surrounding tissue, forcing tumor cells to reprogram their metabolism to adapt to such low glucose conditions. Unlike normal tissue, tumor cells experience glucose starvation, making the targeting of pathways supporting survival during glucose starvation an interesting therapeutic strategy in oncology. Using high-throughput screening, we previously identified small molecules that selectively kill cells exposed to glucose starvation. One of the identified compounds was the kinase inhibitor amuvatinib. To identify new molecules with potential antineoplastic activity, we procured 12 amuvatinib derivatives and tested their selective toxicity towards glucose-starved tumor cells. One of the amuvatinib derivatives, -(2H-1,3-benzodioxol-5-yl)-4-{thieno[3,2-d]pyrimidin-4-yl}piperazine-1-carboxamide, termed compound 6, was found to be efficacious in tumor cells experiencing glucose starvation. In line with the known dependence of glucose-starved cells on the mitochondria, compound 6 inhibits mitochondrial membrane potential. These findings support the concept that tumor cells are dependent on mitochondria under glucose starvation, and bring forth compound 6 as a new molecule with potential antitumor activity for the treatment of glucose-starved tumors.
Topics: Antineoplastic Agents; Cell Line, Tumor; Glucose; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neoplasms; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Thiourea
PubMed: 32033217
DOI: 10.3390/ijms21031041 -
Bioorganic Chemistry Jan 2020Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the...
Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC value of 5.4 µM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC value 0.155 µM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Receptor, Platelet-Derived Growth Factor alpha; Structure-Activity Relationship
PubMed: 31813475
DOI: 10.1016/j.bioorg.2019.103472 -
JAMA Oncology Nov 2019Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high.
IMPORTANCE
Effective treatment options for locally advanced esophageal cancer are limited, and rates of local recurrence after standard chemoradiotherapy remain high.
OBJECTIVE
To evaluate toxic effects, local control, and overall survival rates after chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose to the gross tumor and nodal disease for patients with unresectable locally advanced esophageal cancer.
DESIGN, SETTING, AND PARTICIPANTS
A phase 1/2, single-arm trial was conducted in 46 patients from April 28, 2010, to April 9, 2015 (median follow-up, 52 months [range, 2-86 months]), at a tertiary academic cancer center. Outcomes of the study patients were compared with those of 97 similar patients treated at the same institution from January 10, 2010, to December 5, 2014, as part of the interim analysis. Statistical analysis was performed from December 15, 2018, to February 12, 2019.
INTERVENTIONS
Chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose (50.4 Gy to subclinical areas at risk and 63.0 Gy to the gross tumor and involved nodes, all given in 28 fractions) with concurrent docetaxel and capecitabine or fluorouracil.
MAIN OUTCOMES AND MEASURES
Toxic effects, local (in-field) control, and overall survival rates.
RESULTS
All 46 patients (11 women and 35 men; median age, 65.5 years [range, 37.3-84.4 years]) received per-protocol therapy, as intensity-modulated photon therapy (39 [85%]) or intensity-modulated proton therapy (7 [15%]); 11 patients (24%) ultimately underwent resection. No patients experienced grade 4 or 5 toxic effects; the 10 acute grade 3 toxic events were esophagitis (4), dysphagia (3), and anorexia (3) and the 3 late grade 3 toxic events were all esophageal strictures. The actuarial local recurrence rates were 22% (95% CI, 11%-35%) at 6 months, 30% (95% CI, 18%-44%) at 1 year, and 33% (95% CI, 20%-46%) at 2 years. Overall, 15 patients (33%) experienced local failure, at a median interval of 5 months (range, 1-24 months). The median overall survival time was 21.5 months (range, 2.3-86.4 months). Exploratory comparison with a 97-patient contemporaneous institutional cohort receiving standard-dose (non-simultaneous integrated boost) chemoradiotherapy showed superior local control (hazard ratio, 0.49; 95% CI, 0.26-0.92; P = .03) and overall survival (hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .02) in the group that received chemoradiotherapy with a simultaneous integrated boost.
CONCLUSIONS AND RELEVANCE
These findings suggest that chemoradiotherapy with a simultaneous integrated boost of radiotherapy dose for locally advanced esophageal cancer is well tolerated, with encouraging local control, and thus warrants further study.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT01102088.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy; Docetaxel; Esophageal Neoplasms; Female; Fluorouracil; Humans; Male; Middle Aged; Proton Therapy; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Survival Analysis; Treatment Outcome
PubMed: 31529018
DOI: 10.1001/jamaoncol.2019.2809 -
Journal For Immunotherapy of Cancer Sep 2019Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when...
BACKGROUND
Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting.
METHODS
A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1-20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types.
RESULTS
The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1-19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (P = 0.0001). The median change for longest diameter size for low-dose lesions was - 38.5% compared to 8% in no-dose lesions (P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (P = 0.0004).
CONCLUSIONS
Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.
Topics: Adult; Aged; Aged, 80 and over; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Dose-Response Relationship, Radiation; Female; Follow-Up Studies; Humans; Immunotherapy; Male; Middle Aged; Neoplasms; Prognosis; Prospective Studies; Radiosurgery; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Rate; Young Adult
PubMed: 31484556
DOI: 10.1186/s40425-019-0718-6 -
Biomedicine & Pharmacotherapy =... Oct 2019Multidrug resistance protein 1 (MRP1/ABCC1) actively transports a variety of drugs, toxic molecules and important physiological substrates across the plasma membrane. It...
Multidrug resistance protein 1 (MRP1/ABCC1) actively transports a variety of drugs, toxic molecules and important physiological substrates across the plasma membrane. It can confer broad-spectrum multidrug resistance and can decrease the bioavailability of many important drugs. Substrates of MRP1 include anti-cancer agents, antibiotics, antivirals, antidepressants and anti-inflammatory drugs. Using calcein as a fluorescent reporter in a high content uptake assay, we recently reported the identification of 12 MRP1 inhibitors after screening an anti-cancer library of 386 compounds. Here, we describe the development of a new high content imaging-based uptake assay using doxorubicin as a fluorescent reporter. Screening the same anti-cancer library of 386 compounds, the new assay identified a total of 28 MRP1 inhibitors including 16 inhibitors that have not been previously reported as inhibitors of MRP1. Inhibition of MRP1 activity was confirmed using flow cytometry and confocal microscopy-based transport assays. Six drugs (afatinib, celecoxib, doramapimod, mifepristone, MK-2206 and rosiglitazone) were evaluated for their ability to reverse resistance of MRP1-overexpressing H69AR lung cancer cells against vincristine, doxorubicin and etoposide. Mifepristone and doramapimod were most effective in reversal of resistance against vincristine while mifepristone and rosiglitazone were most successful in resensitizing H69AR cells against doxorubicin. Furthermore, resistance towards etoposide was completely reversed in the presence of celecoxib or doramapimod. Selected drugs were also evaluated for resistance reversal in HEK cells that overexpress P-glycoprotein or breast cancer resistance protein. Our results indicate mifepristone and doramapimod as pan inhibitors of these three drug transporters while celecoxib exhibited selective MRP1 inhibition. Together, our findings signify the importance of MRP1 in drug discovery and demonstrate the effectiveness and value of doxorubicin-based high content screening approach. Anti-cancer agents that exhibit MRP1 inhibition may be used to reverse multidrug resistance or to improve the efficacy and reduce the toxicity of various cancer chemotherapies. On the other hand, anti-cancer drugs that did not interact with MRP1 carry a low risk for developing MRP1-mediated resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Biological Assay; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Fluoresceins; Fluorescent Dyes; HEK293 Cells; High-Throughput Screening Assays; Humans; Multidrug Resistance-Associated Proteins; Protein Transport; Reproducibility of Results
PubMed: 31401398
DOI: 10.1016/j.biopha.2019.109289