Copper(II) Complex Containing 4-Fluorophenoxyacetic Acid Hydrazide and 1,10-Phenanthroline: A Prostate Cancer Cell-Selective and Low-Toxic Copper(II) Compound.

Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men worldwide. The treatment of advanced cases is based on chemotherapy, which lacks specificity and efficacy, due to severe side effects and resistance to the traditional drugs. Copper complexes have shown antitumoral efficacy and low toxicity, being considered a promising class of metal-based drugs for the treatment of malignant neoplasms. Thus, the present study aimed to evaluate the cellular effects of a copper(II) complex with 4-fluorophenoxyacetic acid hydrazide and 1,10-phenanthroline (1) on PCa cell lines, as well as the mutagenic/recombinogenic and anticarcinogenic potential of 1 in Drosophila melanogaster. PNT-2 (non-tumorigenic), LNCaP (hormone-responsive PCa) and PC-3 (androgen-independent PCa) cells were cultured, and cytotoxicity was assessed using the MTT assay. The expression levels of the proliferation markers Ki-67 and Cyclin D1 were analyzed by flow cytometry. Furthermore, the Somatic Mutation and Recombination Test (SMART) and the Epithelial Tumor Test (ETT) were performed. Complex 1 was selective to LNCaP cells, significantly reducing Ki-67 and Cyclin D1 expression levels. Sub-toxic concentrations of complex 1 were defined by the toxicity test in D. melanogaster, and no mutagenic/recombinogenic/carcinogenic effects were observed. Anticarcinogenic potential was observed in D. melanogaster, suggesting modulating activity of the complex 1 against Doxorubicin, a drug used as control by its carcinogenic properties. Therefore, complex 1 is a possible starting point for the development of new antitumor agents for the treatment of PCa.

A selective CuII complex with 4-fluorophenoxyacetic acid hydrazide and phenanthroline displays DNA-cleaving and pro-apoptotic properties in cancer cells.

The thin line between efficacy and toxicity has challenged cancer therapy. As copper is an essential micronutrient and is important to tumor biology, CuII complexes emerged as an alternative to chemotherapy; however, its biological properties need to be better understood. Thus, we report in vitro the antitumor effects of two CuII complexes named [Cu(4-fh)(phen)(ClO4)2] (complex 1) and [Cu(4-nh)(phen)(ClO4)2]·H2O (complex 2), in which 4-fh = 4-fluorophenoxyacetic acid hydrazide; 4-nh = 4-nitrobenzoic hydrazide and phen = 1,10-phenanthroline. Both complexes presented cytotoxic activity against tumor cells, but only complex 1 showed significant selectivity. Complex 1 also induced DNA-damage, led to G0/G1 arrest and triggered apoptosis, which was initiated by an autophagy dysfunction. The significant in vitro selectivity and the action mechanism of complex 1 are noteworthy and reveal this prodrug as promising for anticancer therapy.

Modulating effect of vitamin D3 on the mutagenicity and carcinogenicity of doxorubicin in Drosophila melanogaster and in silico studies.

Vitamin D3 (VD3) deficiency increases DNA damage, while supplementation may exert a pro-oxidant activity, prevent viral infections and formation of tumors. The aim of this study was to investigate the mutagenicity and carcinogenicity of VD3 alone or in combination with doxorubicin (DXR) using the Somatic Mutation and Recombination Test and the Epithelial Tumor Test, both in Drosophila melanogaster. For better understanding of the molecular interactions of VD3 and receptors, in silico analysis were performed with molecular docking associated with molecular dynamics. Findings revealed that VD3 alone did not increase the frequency of mutant spots, but reduced the frequency of mutant spots when co-administered with DXR. In addition, VD3 did not alter the recombinogenic effect of DXR in both ST and HB crosses. VD3 alone did not increase the total frequency of tumor, but significantly reduced the total frequency of tumor when co-administered with DXR. Molecular modeling and molecular dynamics between calcitriol and Ecdysone Receptor (EcR) showed a stable interaction, indicating the possibility of signal transduction between VD3 and EcR. In conclusion, under these experimental conditions, VD3 has modulatory effects on the mutagenicity and carcinogenicity induced by DXR in somatic cells of D. melanogaster and exhibited satisfactory interactions with the EcR.

Parthenolide and its Analogues: A New Potential Strategy for the Treatment of Triple-Negative Breast Tumors.

Triple Negative Breast Cancers (TNBC) are heterogeneous and aggressive pathologies, with distinct morphological and clinical characteristics associated with their genetic diversity, epigenetics, transcriptional changes and aberrant molecular patterns. Treatment with anti-neoplastic drugs exerts systemic effects with low specificity, and incipient improvement in overall survival due to chemoresistance and recurrence. New alternatives for TNBC treatment are urgent and parthenolide or its analogues have been explored. Parthenolide is a sesquiterpene lactone with promising antitumor effects against TNBC cell lines. This review highlights the importance of parthenolide and its analogue drugs in TNBC treatment.

Action of copper(II) complex with ß-diketone and 1,10-phenanthroline (CBP-01) on sarcoma cells and biological effects under cell death.

This work reports the biological evaluation of a copper complex of the type [Cu(O-O)(N-N)ClO4], in which O-O = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (Hbta) and N-N = 1,10-phenanthroline (phen), whose generic name is CBP-01. The cytotoxic effect of CBP-01 was evaluated by resazurin assay and cell proliferation was determined by MTT assay. DNA fragmentation was analyzed by gel electrophoresis. Cell cycle progression was detected through propidium iodide (PI) staining. Apoptosis and autophagy were determined by, respectively, Annexin V and 7-AAD staining and monodansylcadaverine (MDC) staining. The changes in intracellular reactive oxygen species levels were detected by DCFDA analysis. The copper complex CBP-01 showed in vitro antitumor activity with IC50s values of 7.4 µM against Sarcoma 180 and 26.4 against murine myoblast cells, displaying selectivity toward the tumor cell tested in vitro (SI > 3). An increase in reactive oxygen species (ROS) generation was observed, which may be related to the action mechanism of the complex. The complex CBP-01 may induce DNA damage leading cells to accumulate at G0/G1 checkpoint where, apparently, cells that are not able to recover from the damage are driven to cell death. Evidence has shown that cell death is initiated by autophagy dysfunction, culminating in apoptosis induction. The search for new metal-based drugs is focused on overcoming the drawbacks of already used agents such as acquired resistance and non-specificity; thus, the results obtained with CBP-01 show promising effects on cancer cells.

Action of copper(II) complex with ß-diketone and 1,10-phenanthroline (CBP-01) on sarcoma cells and biological effects under cell death

This work reports the biological evaluation of a copper complex of the type [Cu(O–O)(N–N)ClO4], in whichO–O = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (Hbta) and N–N = 1,10-phenanthroline (phen), whose genericname is CBP-01. The cytotoxic effect of CBP-01 was evaluated by resazurin assay and cell proliferation wasdetermined by MTT assay. DNA fragmentation was analyzed by gel electrophoresis. Cell cycle progression wasdetected through propidium iodide (PI) staining. Apoptosis and autophagy were determined by, respectively,Annexin V and 7-AAD staining and monodansylcadaverine (MDC) staining. The changes in intracellular reactiveoxygen species levels were detected by DCFDA analysis. The copper complex CBP-01 showed in vitro antitumoractivity with IC50s values of 7.4µM against Sarcoma 180 and 26.4 against murine myoblast cells, displayingselectivity toward the tumor cell tested in vitro (SI > 3). An increase in reactive oxygen species (ROS) gen-eration was observed, which may be related to the action mechanism of the complex. The complex CBP-01 mayinduce DNA damage leading cells to accumulate at G0/G1 checkpoint where, apparently, cells that are not ableto recover from the damage are driven to cell death. Evidence has shown that cell death is initiated by autophagydysfunction, culminating in apoptosis induction. The search for new metal-based drugs is focused on overcomingthe drawbacks of already used agents such as acquired resistance and non-specificity; thus, the results obtainedwith CBP-01 show promising effects on cancer cells.

Action of copper(II) complex with ß-diketone and 1,10-phenanthroline (CBP-01) on sarcoma cells and biological effects under cell death

This work reports the biological evaluation of a copper complex of the type [Cu(O–O)(N–N)ClO4], in whichO–O = 4,4,4-trifluoro-1-phenyl-1,3-butanedione (Hbta) and N–N = 1,10-phenanthroline (phen), whose genericname is CBP-01. The cytotoxic effect of CBP-01 was evaluated by resazurin assay and cell proliferation wasdetermined by MTT assay. DNA fragmentation was analyzed by gel electrophoresis. Cell cycle progression wasdetected through propidium iodide (PI) staining. Apoptosis and autophagy were determined by, respectively,Annexin V and 7-AAD staining and monodansylcadaverine (MDC) staining. The changes in intracellular reactiveoxygen species levels were detected by DCFDA analysis. The copper complex CBP-01 showed in vitro antitumoractivity with IC50s values of 7.4µM against Sarcoma 180 and 26.4 against murine myoblast cells, displayingselectivity toward the tumor cell tested in vitro (SI > 3). An increase in reactive oxygen species (ROS) gen-eration was observed, which may be related to the action mechanism of the complex. The complex CBP-01 mayinduce DNA damage leading cells to accumulate at G0/G1 checkpoint where, apparently, cells that are not ableto recover from the damage are driven to cell death. Evidence has shown that cell death is initiated by autophagydysfunction, culminating in apoptosis induction. The search for new metal-based drugs is focused on overcomingthe drawbacks of already used agents such as acquired resistance and non-specificity; thus, the results obtainedwith CBP-01 show promising effects on cancer cells.