Overview of Antabuse® (Disulfiram) in Radiation and Cancer Biology.
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ABSTRACT:
SUBMITTER: Jia Y
PROVIDER: S-EPMC8146747 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In mammal myocytes, endothelial cells and inner ear cells, ferlins are proteins involved in membrane processes such as fusion, recycling, endo- and exocytosis. They harbour several C2 domains allowing their interaction with phospholipids. The expression of several Ferlin genes was described as altered in several tumoural tissues. Intriguingly, beyond a simple alteration, myoferlin, otoferlin and Fer1L4 expressions were negatively correlated with patient survival in some cancer types. Therefore, it can be assumed that membrane biology is of extreme importance for cell survival and signalling, making Ferlin proteins core machinery indispensable for cancer cell adaptation to hostile environments. The evidences suggest that myoferlin, when overexpressed, enhances cancer cell proliferation, migration and metabolism by affecting various aspects of membrane biology. Targeting myoferlin using pharmacological compounds, gene transfer technology, or interfering RNA is now considered as an emerging therapeutic strategy.
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Project description:Overcoming the radiosensitivity of chondrosarcoma (CS), the second most common primary bone tumor, is needed. Radioresistance is attributed to cancer stem cells (CSCs) in many malignancies. Disulfiram (DSF), an FDA-approved anti-alcoholism drug, complexed with Cu (DSF/Cu) can radiosensitize epithelial CSCs. This prompted us to investigate the radiosensitizing effect of DSF/Cu on CS CSCs (CCSCs). The radiosensitizing effects of DSF/Cu on CCSCs were investigated in vitro using cell lines SW1353 and CS-1. Stemness was identified independently by flow cytometry for CCSCs (ALDH+CD133+), sphere-forming ability, and Western blot analysis of stemness gene protein expression. The radiosensitizing effect of DSF/Cu was studied in an orthotopic CS xenograft mouse model by analyzing xenograft growth and residual xenografts for stemness. CCSCs were found to be resistant to single-dose (IR) and fractionated irradiation (FIR). IR and FIR increased CS stemness. Combined with DSF/Cu in vitro and in vivo, IR and FIR eliminated CS stemness. RT + DSF/Cu was safer and more effective than either RT ± DSF in inhibiting growth of orthotopic CS xenografts. In conclusion, DSF/Cu radiosensitizes CCSCs. These results can be translated into clinical trials for CS patients requiring RT for improved outcomes.
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Project description:BackgroundFew studies have investigated whether there is a difference in local control or overall survival rates following treatment with robotic stereotactic body radiation therapy (SBRT) with or without prior fiducial marker implantation. Our study aimed to investigate this in patients with primary or secondary lung tumors.MethodsA retrospective study was conducted at the Institut de Cancérologie de Lorraine of patients treated for primary lung cancer or pulmonary oligometastases with SBRT from January 2013 to July 2016. We included patients at least 18 years old who had stage I non-small cell lung cancer (NSCLC) or lung metastases and a follow-up of at least 1 month.ResultsA total of 294 patients were included. Tumors included 122 lung metastases, 89 stage I NSCLC, and 83 non-histologically confirmed lung lesions. The tracking methods were Synchrony® in 191 cases (119 gold seeds and 72 coils) and Xsight® Spine with 4D computed tomography in 103 cases. Median follow-up was 31.6 months [interquartile range (IQR), 18.1-50.2 months]. The two- and five-year probability of local control were respectively 92.22% [95% confidence interval (CI): 0.89-0.95] and 85.35% (95% CI: 0.79-0.99). The two- and five-year probability of overall survival were respectively 87.46% and 72.77% (P=0.586). Local control rates did not significantly differ between techniques at 2 and 5 years (P=0.685) (gold seeds, coils or Xsight® Spine) within tumors grouped by location, gross tumor volume (GTV) (respectively P=0.9, P=0.7, and P=0.4), planning target volume (PTV) (respectively P=0.4, P=0.9, and P=0.7), or PTV/GTV ratio (respectively P=0.6, P=0.6, and P=0.5). Metastasis-free survival and Overall survival rates did not significantly differ between techniques at 2 and 5 years (P=0.664 and P=0.586, respectively). There were no grade 4 or 5 toxicities and only one grade 3 pneumonitis and one grade 3 pneumothorax.ConclusionsFiducial-less SBRT using Xsight® Spine is a safe alternative to Synchrony® using gold seeds or coils, with comparable local control and overall survival rates and a similar toxicity profile.
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Project description:Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5+ intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident.
| S-EPMC9061966 | biostudies-literature
Project description:BackgroundCurrent treatment options for castration- and treatment-resistant prostate cancer are limited and novel approaches are desperately needed. Our recent results from a systematic chemical biology sensitivity screen covering most known drugs and drug-like molecules indicated that aldehyde dehydrogenase inhibitor disulfiram is one of the most potent cancer-specific inhibitors of prostate cancer cell growth, including TMPRSS2-ERG fusion positive cancers. However, the results revealed that disulfiram alone does not block tumor growth in vivo nor induce apoptosis in vitro, indicating that combinatorial approaches may be required to enhance the anti-neoplastic effects.Methods and findingsIn this study, we utilized a chemical biology drug sensitivity screen to explore disulfiram mechanistic details and to identify compounds potentiating the effect of disulfiram in TMPRSS2-ERG fusion positive prostate cancer cells. In total, 3357 compounds including current chemotherapeutic agents as well as drug-like small molecular compounds were screened alone and in combination with disulfiram. Interestingly, the results indicated that androgenic and antioxidative compounds antagonized disulfiram effect whereas inhibitors of receptor tyrosine kinase, proteasome, topoisomerase II, glucosylceramide synthase or cell cycle were among compounds sensitizing prostate cancer cells to disulfiram. The combination of disulfiram and an antiangiogenic agent sunitinib was studied in more detail, since both are already in clinical use in humans. Disulfiram-sunitinib combination induced apoptosis and reduced androgen receptor protein expression more than either of the compounds alone. Moreover, combinatorial exposure reduced metastatic characteristics such as cell migration and 3D cell invasion as well as induced epithelial differentiation shown as elevated E-cadherin expression.ConclusionsTaken together, our results propose novel combinatorial approaches to inhibit prostate cancer cell growth. Disulfiram-sunitinib combination was identified as one of the potent synergistic approaches. Since sunitinib alone has been reported to lack efficacy in prostate cancer clinical trials, our results provide a rationale for novel combinatorial approach to target prostate cancer more efficiently.
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Project description:Although the incidence of small cell lung cancer (SCLC) has declined during the past 30 years, it remains a frustrating disease to research and treat. Numerous attempts to enhance the anti-tumor effects of traditional chemotherapy for SCLC have not been successful. For any tumor to become cancerous, various genetic mutations and biologic alterations must occur in the cell that, when combined, render it a malignant neoplasm. New and novel therapies based on understanding these mechanisms of transformation are needed. Herein we provide an in-depth view of some of the genomic alterations in SCLC that have emerged as potential targets for therapeutic intervention.
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Project description:ObjectiveTo introduce a novel technology currently under final development before regulatory approvals for the furtherment of cataract surgery, using the FemtoMatrix® laser system, and to demonstrate its safety and efficacy as compared to standard ultrasound phacoemulsification.MethodsThirty-three patients with bilateral cataracts were operated on with one eye undergoing PhotoEmulsification® treatment on the FemtoMatrix® device and the contralateral eye receiving the control procedure, i.e., standard ultrasound phacoemulsification treatment. The number of "zero-phaco" procedures (denoting that I/A alone was sufficient to aspirate the lens fragments and that no ultrasound energy was needed) was recorded and Effective Phaco Time (EPT) values were compared. The patient follow-up was 3 months.ResultsThirty-three eyes from a population with a mean cataract grade of 2.6 were treated on the FemtoMatrix®, of which 29 were "zero-phaco" (88%). All patients were operated on by a single surgeon who was a relative novice to the technology (63 patients treated prior to this study). Conversely, of the 33 fellow eyes who underwent standard ultrasound phacoemulsification, none were zero-phaco (0%) - all required varying degrees of ultrasound energy to make lens aspiration possible. The mean EPT was significantly lower in the PhotoEmulsification® laser group (0.2 ± 0.8 s) than in the phaco group (1.3 ± 1.2 s) (p < 0.0001). The safety profiles of the two procedures were comparable, with no device-related adverse events noted.ConclusionFemtoMatrix® is a promising femtosecond laser platform that, when compared to phacoemulsification, significantly decreases or eliminates EPT altogether. The system is used to perform PhotoEmulsification®, making zero-phaco cataract procedures feasible including in high-grade cataracts (>3). It enables personalized treatment by automatically measuring and adapting the laser energy required to obtain the most efficient cutting of the crystalline lens. This new technology appears to be safe and effective in cataract surgery.
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Project description:BackgroundMammaPrint® is a microarray-based gene expression test cleared by the US Food and Drug Administration to assess recurrence risk in early-stage breast cancer, aimed to guide physicians in making neoadjuvant and adjuvant treatment decisions. The increase in the incidence of invasive lobular carcinomas (ILCs) over the past decades and the modest representation of ILC in the MammaPrint development data set calls for a stratified survival analysis dedicated to this specific subgroup.Study aimThe current study aimed to validate the prognostic value of the MammaPrint test for breast cancer patients with early-stage ILCs.Materials and methodsUnivariate and multivariate survival associations for overall survival (OS), distant metastasis-free interval (DMFI), and distant metastasis-free survival (DMFS) were studied in a study population of 217 early-stage ILC breast cancer patients from five different clinical studies.Results and discussionA significant association between MammaPrint High Risk and poor clinical outcome was shown for OS, DMFI, and DMFS. A subanalysis was performed on the lymph node-negative study population. In the lymph node-negative study population, we report an up to 11 times higher change in the diagnosis of an event in the MammaPrint High Risk group. For DMFI, the reported hazard ratio is 11.1 (95% confidence interval = 2.3-53.0).ConclusionStudy results validate MammaPrint as an independent factor for breast cancer patients with early-stage invasive lobular breast cancer. Hazard ratios up to 11 in multivariate analyses emphasize the independent value of MammaPrint, specifically in lymph node-negative ILC breast cancers.
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Project description:BackgroundRehabilitation robotics is a field of study which aims to understand and augment rehabilitation through the use of robotics devices.ObjectiveThis proof of concept study aimed to test the safety (no. adverse events, incidence of infection), feasibility (program demand, adherence, participant satisfaction) and efficacy (Peak Oxygen uptake (VO2peak), 6-min walk test, gait speeds, Canadian Occupational Performance Measure, quality of life) of Lokomat® and Armeo®Spring training in children and adolescents and young adults (AYAs) during or soon after cancer treatment.MethodThis was a 6-week single arm pre-post study. Cancer patients with significant musculoskeletal, neurological, gait and/or upper limb deficiency aged 5 to 25 years were recruited. The rehabilitation program included access to two robotic orthoses: the Lokomat® and/or Armeo®Spring. Robotic devices utilised real-time biofeedback and computer games to engage and guide participants through a repetitive functional range of movement aimed at improving functional deficiencies. Progressive increases in exercise intensity and duration were encouraged.ResultsTwentey-eight participants were approached for study; twenty-one consented. Seventy-six percent completed the six-week intervention with an overall adherence of 83%. The mean participant satisfaction score was 8.8/10. Forty-nine adverse events were recorded throughout the course of the study, forty-five grade 1, three grade 2 and one grade 3. No adverse events led to withdrawal from the study. Preliminary efficacy results indicate large beneficial effects on VO2peak (r = 0.63), 10 m comfortable pace walk (r = 0.51) and maximal pace walk (r = 0.60), 6-min walk test (r = 0.60), maximal back and leg strength (r = 0.71), trunk flexibility (r = 0.60), The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) (r = 0.61), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT F) r = 0.53 and the Canadian Occupational Performance Measure, satisfaction (r = 0.88) and performance scores (r = 0.83), and moderate beneficial effects on Leisure Score Index (LSI) (r = 0.30).ConclusionOur results suggest that Lokomat® and Armeo®Spring training is safe and feasible for use in children and AYAs who are currently undergoing or have recently completed cancer therapy. A larger controlled trial investigating the efficacy of robotics rehabilitation in this cohort is warranted.
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Project description:PurposeCSMed® wound dressing, a dressing with various herb extracts, was tested for its therapeutic effect in radiation dermatitis of breast and head-and-neck cancer patients.MethodsThis study included 20 breast cancer patients and 10 head-and-neck cancer patients. Half of the irradiated area was covered with CSMed® and the other half was under routine treatment. The severity of radiation dermatitis was evaluated with radiation therapy oncology group (RTOG) grade throughout the treatment and the follow-up period. The RTOG grade between the dressed and undressed area were compared to illustrate the therapeutic effect of CSMed® dressing.ResultsThe results showed that CSMed® dressed area had significant lower RTOG score at 3-7 weeks and final record during the treatment, and 1-3 weeks during follow-up than undressed area.ConclusionsThis indicated that CSMed® can delay the onset, reduce the severity, and enhance healing of radiation dermatitis. CSMed® can be used for prophylaxis and management of radiation dermatitis.
| S-EPMC10891181 | biostudies-literature