Disulfiram and Copper Ions Kill Mycobacterium tuberculosis in a Synergistic Manner

Tuberculosis is a severe disease affecting millions worldwide. Unfortunately, treatment strategies are hampered both by the prohibitively long treatment regimen and the rise of drug-resistant strains. Significant effort has been expended in the search for new treatments, but few options have successfully emerged, and new treatment modalities are desperately needed. Recently, there has been growing interest in the synergistic antibacterial effects of copper ions (Cu^II/I) in combination with certain small molecular compounds, and we have previously reported development of a drug screening strategy to harness the intrinsic bactericidal properties of Cu^II/I. Here, we describe the copper-dependent antimycobacterial properties of disulfiram, an FDA-approved and well-tolerated sobriety aid. Disulfiram was inhibitory to mycobacteria only in the presence of Cu^II/I and exerted its bactericidal activity well below the active concentration of Cu^II/I or disulfiram alone. No other physiologically relevant bivalent transition metals (e.g., Fe^II, Ni^II, Mn^II, and Co^II) exhibited this effect. We demonstrate that the movement of the disulfiram-copper complex across the cell envelope is porin independent and can inhibit intracellular protein functions. Additionally, the complex is able to synergistically induce intracellular copper stress responses significantly more than Cu^II/I alone. Our data suggest that by complexing with disulfiram, Cu^II/I is likely allowed unfettered access to vulnerable intracellular components, bypassing the normally sufficient copper homeostatic machinery. Overall, the synergistic antibacterial activity of Cu^II/I and disulfiram reveals the susceptibility of the copper homeostasis system of Mycobacterium tuberculosis to chemical attacks and establishes compounds that act in concert with copper as a new class of bacterial inhibitors.     

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Journal of Neuro-Oncology - Smoking is agreed to be a major health risk factor, but it is debated whether it has an influence on perioperative adverse events (AEs) in elective cranial tumor...     

Hypofractionated radiotherapy and adjuvant chemotherapy do not increase radiation-induced dermatitis in breast cancer patients

Purpose

Radiation-induced dermatitis is a common side effect of breast irradiation, with hypofractionation being a well-known risk factor. In the context of the widespread adoption of hypofractionated breast radiotherapy, we evaluated the effect of hypofractionated radiotherapy on the incidence of skin toxicity in patients receiving adjuvant chemotherapy.

Patients and Methods

We retrospectively reviewed the records of patients with breast cancer treated from 2004 to 2006 at a single institution. Patients undergoing lumpectomy with or without adjuvant chemotherapy followed by hypofractionated radiotherapy consisting of 42.4 Gy in 16 fractions were included in the study. Using cosmetic and skin toxicity scales, all patients were evaluated weekly during treatment and at scheduled follow-up visits with the radiation oncologist.

Results

During the study period, 162 patients underwent radiotherapy, and 30% of those (n = 48) received chemotherapy. Radiotherapy boost to the tumour bed was more common in the chemotherapy group [n = 20 (42%)] than in the radiotherapy-alone group [n = 30 (26%)]. We observed no statistically significant difference between the groups with regard to acute skin toxicity of grade 3 or higher (2.1% in the chemotherapy group vs. 4.4% in the radiation-alone group, p = 0.67) or of grades 1–2 toxicity (62.5% vs. 51.7% respectively, p = 0.23). There was also no significant difference in late grade 3 or higher skin toxicity between the groups (2.1% vs. 0% respectively, p = 0.30) or in grades 1–2 toxicity (20.8% vs. 25.5% respectively, p = 0.69). Similarly, excellent or good cosmetic result scores were similar in both groups (p = 0.80)

Conclusions

In our single-institution review, we observed no adverse effects of chemotherapy in combination with hypofractionated whole-breast irradiation. Further investigations are necessary to better elucidate the effects of chemotherapy on skin toxicity in the context of hypofractionated irradiation.     

Toxic effects of Carthamus tinctorius L. (Safflower) extract on mouse spermatogenesis

Objective

To evaluate the effects of aqueous extract of Carthamus tinctorius L., also named safflower, on mouse spermatogenesis.

Methods

Sixteen adult male NMRI mice were used. Experimental group received Carthamus tinctorius L. extract at the dose of 200 mg/kg for 35 consecutive days and control group received only distilled water. Testicular histopathology, morphometric analysis and spermatogenesis assessments were performed for evaluation of the Carthamus tinctorius L. extract effects on testis.

Results

Histopathological criteria such as epithelial vacuolization, sloughing of germ and detachment were significantly decreased in Carthamus tinctorius L. treated mice (p < 0.001). Carthamus tinctorius L. extract induced formation of multinucleated giant cells in the germinal epithelium. Carthamus tinctorius L. extract also caused a significant decrease in seminiferous tubule diameter, seminiferous epithelium height and maturation arrest (p < 0.001).

Conclusion

Carthamus tinctorius L. extract has toxic effects on mouse testicular tissue, and recommended to use it with caution if there is a reproductive problem.