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Journal of the Formosan Medical... Aug 2023The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC).
PURPOSE
The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC).
METHODS
Firstly, we used qRT-PCR and Western blot to compare the difference in the expression of ZC3H13 between normal thyroid epithelial cells and PTC cell lines. Then, ZC3H13 overexpression/knockout thyroid cancer cells were constructed by lentivirus transfection, and the effects of overexpression of ZC3H13 on the proliferation, migration and invasion of PTC cells were detected by CCK8 and transwell experiments. Lastly, MeRIP-qPCR, RIP and o Actinomycin D were used to verify that ZC3H13 regulated the expression of downstream target gene IQGAP1 through m6A modification.
RESULTS
ZC3H13 expression was decreased in PTC cell lines BCPAP, KTC-1, k1, HTH83, and TPC-1. Proliferation, invasion, and migration of PTC cells were inhibited by overexpressed ZC3H13 but increased by knockdown of ZC3H13. IQGAP1 expression was suppressed by ZC3H13 overexpression but enhanced by ZC3H13 knockdown. In ZC3H13-overexpressed PTC cells, the m6A level of IQGAP1 mRNA was increased, and the IQGAP1 mRNA expression was decreased with the increasing time of Actinomycin D treatment. YTHDF2 enriched more IQGAP1 mRNA than IgG and knockdown of YTHDF2 reversed the effect of ZC3H13 overexpression on IQGAP1 mRNA stability. The xenograft tumor experiment in nude mice confirmed that the overexpression of ZC3H13 inhibited tumor growth, while overexpression of IQGAP1 could reverse the inhibitory effect of ZC3H13 overexpression on tumor growth.
CONCLUSION
ZC3H13 mediates IQGAP1 mRNA degradation by promoting m6A modification of IQGAP1 mRNA, this provides a prospective therapeutic target for PTC.
Topics: Mice; Animals; Humans; Thyroid Cancer, Papillary; MicroRNAs; Mice, Nude; Dactinomycin; Cell Line, Tumor; Cell Proliferation; Neoplasm Invasiveness; Cell Movement; Thyroid Neoplasms; RNA, Messenger; Gene Expression Regulation, Neoplastic; Nuclear Proteins; RNA-Binding Proteins
PubMed: 36739231
DOI: 10.1016/j.jfma.2022.12.019 -
Mini Reviews in Medicinal Chemistry 2020Natural products form a significant portion of medicinal agents that are currently used for the management of cancer. All these natural products have unique structures... (Review)
Review
Natural products form a significant portion of medicinal agents that are currently used for the management of cancer. All these natural products have unique structures along with diverse action mechanisms with the capacity to interact with different therapeutic targets of several complex disorders. Although plants contribute as a major source of natural products with anti-cancer potential, the marine environment and microbes have also bestowed some substantial chemotherapeutic agents. A few examples of anti-cancer agents of natural origin include vincristine, vinblastine, paclitaxel, camptothecin and topotecan obtained from plants, bryostatins, sarcodictyin and cytarabine from marine organisms and bleomycin and doxorubicin from micro-organisms (dactinomycin, bleomycin and doxorubicin). The incredible diversity in the chemical structures and biological properties of compounds obtained from million species of plants, marine organisms and microorganisms present in nature has commenced a new era of potential therapeutic anti-cancer agents.
Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Products; Heterocyclic Compounds; Humans; Molecular Structure; Neoplasms
PubMed: 32048967
DOI: 10.2174/1389557520666200212104742 -
Cancer Jan 2022The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective.
METHODS
A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs.
RESULTS
Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices.
CONCLUSIONS
Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions.
LAY SUMMARY
Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cost-Benefit Analysis; Cyclophosphamide; Dactinomycin; Drug Costs; Humans; Rhabdomyosarcoma; Vincristine
PubMed: 34623638
DOI: 10.1002/cncr.33917 -
Pediatric Blood & Cancer May 2023Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard...
Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group.
BACKGROUND
Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard Children's Oncology Group (COG) chemotherapy backbone of vincristine, actinomycin-D, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) in children with intermediate-risk (IR) RMS.
METHODS
The feasibility phase of the COG IR-RMS trial, ARST1431 (NCT02567435), assigned 10 patients to receive 15 mg/m /dose (dose level 1) of temsirolimus on days 1, 8, and 15 of each of three weekly VAC and VI cycles for the first 12 weeks of induction chemotherapy. The primary endpoint of the feasibility phase was to establish the safe dose and safety of combining temsirolimus with VAC/VI. The combination regimen was deemed feasible if less than 40% of patients developed a priori defined nonhematological dose-limiting toxicities (DLTs).
RESULTS
Ten patients (seven males and three females; median age = 4.5 years [range: 0.2-14.4 years]) with IR-RMS were enrolled and received dose level 1 of temsirolimus. Eight patients had FOXO1-negative disease, while two had FOXO1-positive disease. Two patients had metastatic disease. Of 10 patients, two developed DLTs: grade 3 oral mucositis and pneumonitis. Four patients (40%) had grade 4 neutropenia. No treatment-related mortality occurred. The median duration of the completion of the feasibility phase was 12.1 weeks (range: 11.7-15 weeks).
CONCLUSIONS
Weekly temsirolimus at 15 mg/m /dose during VAC/VI chemotherapy was feasible and well tolerated. The efficacy of this regimen is currently being tested in a phase III randomized trial against VAC/VI chemotherapy alone in the ARST1431 trial.
PubMed: 37243336
DOI: 10.1002/pbc.30436 -
Briefings in Bioinformatics May 2022Identifying new lead molecules to treat cancer requires more than a decade of dedicated effort. Before selected drug candidates are used in the clinic, their anti-cancer...
Identifying new lead molecules to treat cancer requires more than a decade of dedicated effort. Before selected drug candidates are used in the clinic, their anti-cancer activity is generally validated by in vitro cellular experiments. Therefore, accurate prediction of cancer drug response is a critical and challenging task for anti-cancer drugs design and precision medicine. With the development of pharmacogenomics, the combination of efficient drug feature extraction methods and omics data has made it possible to use computational models to assist in drug response prediction. In this study, we propose DeepTTA, a novel end-to-end deep learning model that utilizes transformer for drug representation learning and a multilayer neural network for transcriptomic data prediction of the anti-cancer drug responses. Specifically, DeepTTA uses transcriptomic gene expression data and chemical substructures of drugs for drug response prediction. Compared to existing methods, DeepTTA achieved higher performance in terms of root mean square error, Pearson correlation coefficient and Spearman's rank correlation coefficient on multiple test sets. Moreover, we discovered that anti-cancer drugs bortezomib and dactinomycin provide a potential therapeutic option with multiple clinical indications. With its excellent performance, DeepTTA is expected to be an effective method in cancer drug design.
Topics: Antineoplastic Agents; Humans; Neoplasms; Neural Networks, Computer; Precision Medicine; Transcriptome
PubMed: 35348595
DOI: 10.1093/bib/bbac100 -
Leukemia Sep 2021Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML...
Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Moreover, the prognosis is particularly poor in elderly and unfit patients, mainly because they cannot receive intensive treatment. Therefore, alternative treatment strategies are needed. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. Here, we describe the results of a single-center phase 2 pilot study investigating the safety and efficacy of single-agent dactinomycin in relapsed/refractory NPM1-mutated adult AML patients, demonstrating that this drug can induce complete responses and is relatively well tolerated. We also provide evidence that the activity of dactinomycin associates with nucleolar stress both in vitro and in vivo in patients. Finally, we show that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress. In conclusion, we establish that dactinomycin is a potential therapeutic alternative in relapsed/refractory NPM1-mutated AML that deserves further investigation in larger clinical studies.
Topics: Aged; Antibiotics, Antineoplastic; Cell Nucleolus; Dactinomycin; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Nuclear Proteins; Nucleophosmin; Pilot Projects; Prognosis; Remission Induction; Salvage Therapy
PubMed: 33654209
DOI: 10.1038/s41375-021-01192-7 -
Journal of Clinical Oncology : Official... Nov 2022Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
PATIENTS AND METHODS
In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible.
RESULTS
MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% ( < .0001) and 3-year OS 60.0% versus 26.0% ( < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance.
CONCLUSION
Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.
Topics: Child; Humans; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Rhabdomyosarcoma; Sarcoma; Ifosfamide; Vincristine; Cyclophosphamide; Dactinomycin; Doxorubicin; Neoplasms, Second Primary
PubMed: 35709412
DOI: 10.1200/JCO.21.02981 -
Proceedings of the National Academy of... Aug 2021Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only...
Death receptor-mediated apoptosis requires the mitochondrial apoptosis pathway in many mammalian cells. In response to death receptor signaling, the truncated BH3-only protein BID can activate the proapoptotic BCL-2 proteins BAX and BAK and trigger the permeabilization of the mitochondria. BAX and BAK are inhibited by prosurvival BCL-2 proteins through retrotranslocation from the mitochondria into the cytosol, but a specific resistance mechanism to truncated BID-dependent apoptosis is unknown. Here, we report that hexokinase 1 and hexokinase 2 inhibit the apoptosis activator truncated BID as well as the effectors BAX and BAK by retrotranslocation from the mitochondria into the cytosol. BCL-2 protein shuttling and protection from TRAIL- and FasL-induced cell death requires mitochondrial hexokinase localization and interactions with the BH3 motifs of BCL-2 proteins but not glucose phosphorylation. Together, our work establishes hexokinase-dependent retrotranslocation of truncated BID as a selective protective mechanism against death receptor-induced apoptosis on the mitochondria.
Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Apoptosis; Cell Line; Cyclosporine; Dactinomycin; Doxorubicin; Enzyme Inhibitors; Fas Ligand Protein; Gene Deletion; Gene Expression Regulation, Enzymologic; Hexokinase; Humans; Mitochondria; TNF-Related Apoptosis-Inducing Ligand; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 34385311
DOI: 10.1073/pnas.2021175118 -
International Journal of Cancer Apr 2023In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a... (Randomized Controlled Trial)
Randomized Controlled Trial
Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France.
In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m , ifosfamide = 59.4 g/m ) and 88 in VAI (ifosfamide = 97.1 g/m ). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide).
Topics: Male; Humans; Female; Adolescent; Sarcoma, Ewing; Ifosfamide; Dactinomycin; Vincristine; Etoposide; Bone Neoplasms; Neoplasm Recurrence, Local; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; France
PubMed: 36250317
DOI: 10.1002/ijc.34326 -
PeerJ 2023Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore...
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) is one of the world's most devastating contagious diseases and is caused by the MDR- (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, and studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X (act-X) and actinomycin-D (act-D), from the strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia).
METHODS
The anti-TB activity of the isolated actinomycins was assessed using the Mtb H37Ra, (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands.
RESULTS
results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-Xand act-D respectively. The molecular dynamics (MD) results demonstrated that act-X and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X was more potent than act-D.
CONCLUSION
In conclusion, our results suggest that both actinomycins X and D are highly potent anti-TB drug candidates. We show that act-Xis better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.
Topics: Humans; Antitubercular Agents; BCG Vaccine; Dactinomycin; Molecular Docking Simulation; Protein Kinases; Tuberculosis, Multidrug-Resistant
PubMed: 36935926
DOI: 10.7717/peerj.14502