The impact of biomolecule interactions on the cytotoxic effects of rhenium(I) tricarbonyl complexes.

Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 µM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 µM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA).

Synthesis and Cytotoxicity Studies of Br-Substituted Salphen Organic Compounds.

We present the synthesis and characterization of organic Salphen compounds containing bromine substituents at the para/ortho-para positions, in their symmetric and non-symmetric versions, and describe the X-ray structure and full characterization for the new unsymmetrical varieties. We report for the first time antiproliferative activity in metal-free brominated Salphen compounds, by evaluations in four human cancer cell lines, cervix (HeLa), prostate (PC-3), lung (A549) and colon (LS 180) and one non-cancerous counterpart (ARPE-19). We assessed in vitro cell viability against controls using the MTT assay ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)) and determined the concentration required for 50 % growth inhibition (IC50 ), together with their selectivity vs. non-cancerous cells. We found promising results against prostate (9.6 µM) and colon (13.5 µM) adenocarcinoma cells. We also found a tradeoff between selectivity (up to 3-fold vs. ARPE-19) and inhibition, depending upon the symmetry and bromine-substitution of the molecules, showing up to 20-fold higher selectivity vs. doxorubicin controls.

Health litigation and cancer survival in patients treated in the public health system in a large Brazilian city, 2014-2019.

BACKGROUND: Litigation for health care, also known as health judicialization, is frequent in Brazil. It involves recourse to the court system to access health services. The study aimed to evaluate whether cancer patients in Belo Horizonte, Minas Gerais, Brazil, increased their overall survival by increasing access to certain drugs or treatments through litigation, controlling for the effect of demographic and disease-related variables. METHODS: A retrospective cohort study was conducted. Patients with breast, prostate, brain, lung, or colon cancers from 2014 to 2019 were included. Survival analysis was performed using the Cox proportional hazards model. RESULTS: In the multivariate analysis, litigation was significantly associated with increased survival in cancers of breast (HR = 0.51, 95%CI 0.33-0.80), prostate (HR = 0.50, 95%CI 0.30-0.85), colon (HR = 0.59, 95%CI 0.38-0.93), and lung (HR = 0.36, 95%CI 0.22-0.60). Five-year survival rates of patients who sued for treatment were 97.8%, 88.7%, 59.3%, and 26.0%, compared to median survival of 95.7%, 78.7%, 41.2%, and 2.4%, respectively, among patient that did not resort to court action. The study suggests that litigation for access to cancer treatment may represent a step forward in obtaining more effective treatment. This study´s main limitations are the lack of patients´ clinical information for use as control variables and the lack of variables to assess patients´ quality of life. The study also found that many cases involved claims that could have been solved by administrative rather than legal action. Some claims thus reflect the lack of adequate administrative procedures. CONCLUSION: When based on scientific evidence, access to new therapies, combined with other technologies already available, can favor patient survival. Access to new therapies through litigation may increase health inequalities since low-income patients have limited access to legal recourse against the State to meet their needs. The timely approval of new effective therapies can mitigate the judicialization of cancer treatment.

Draft genome sequence of the cyanobacterium Sphaerospermopsis aphanizomenoides BCCUSP55 from the Brazilian semiarid region reveals potential for anti-cancer applications.

Sphaerospermopsis aphanizomenoides is a filamentous nitrogen-fixing and bloom-forming cyanobacterium, which biomass can fertilize natural water with nutrients, especially through nitrogen fixation. The Sphaerospermopsis aphanizomenoides strain BCCUSP55 was previously isolated from a water supply reservoir in the Brazilian semiarid region, and its draft genome assembly coupled with the gene contents are reported here. The obtained BCCUSP55 draft genome comprised 254 scaffolds with a genome size estimated of 6,096,273 bp. In addition, it has 5250 predicted coding sequences (CDS) and the G + C content is 38.5%. Further, the BCCUSP55 draft genome presented the putative nocuolin A gene complete cluster, a natural oxadiazine that triggers apoptosis in human cancer cells. Thus, our results contribute to extend the knowledge on the genus Sphaerospermopsis and reveal its biotechnological potential.

Detection of anti-cancer drugs and metabolites in the effluents from a large Brazilian cancer hospital and an evaluation of ecotoxicology.

The use of chemotherapy agents has been growing worldwide, due to the increase number of cancer cases. In several countries, mainly in Europe countries, these drugs have been detected in hospitals and municipal wastewaters. In Brazil this issue is poorly explored. The main goal of this study was to assess the presence of three anti-cancer drugs, 5-fluorouracil (5-FU), gemcitabine (GEM) and cyclophosphamide (CP), and two metabolites, alpha-fluoro-beta-alanine (3-NH2-F) and 2'-deoxy-2',2'-difluorouridine (2-DOH-DiF), in effluents from a large cancer hospital, in the municipal wastewater treatment plant (WWTP) influent and effluent, and also to evaluate toxicity of the mixtures of these compounds by ecotoxicological testing in zebrafish. The sample collections were performed in Barretos Cancer Hospital of the large cancer center in Brazil. After each collection, the samples were filtered for subsequent Liquid Chromatography Mass Spectrometry analysis. The presence of CP, GEM, and both metabolites (3-NH2-F and 2-DOH-DiF) were detected in the hospital wastewater and the WWTP influent. Three drugs, GEM, 2-DOH-DiF and CP, were detected in the WWTP effluent. Two drugs were detected below the limit of quantification, 2-DOH-DiF:

Inhibitors of lipogenic enzymes as a potential therapy against cancer.

Cancer cells rely on several metabolic pathways such as lipid metabolism to meet the increase in energy demand, cell division, and growth and successfully adapt to challenging environments. Fatty acid synthesis is therefore commonly enhanced in many cancer cell lines. Thus, relevant efforts are being made by the scientific community to inhibit the enzymes involved in lipid metabolism to disrupt cancer cell proliferation. We review the rapidly expanding body of inhibitors that target lipid metabolism, their side effects, and current status in clinical trials as potential therapeutic approaches against cancer. We focus on their molecular, biochemical and structural properties, selectivity and effectiveness and discuss their potential role as antitumor drugs.

Guide for Selection of Relevant Cell Lines During the Evaluation of new Anti-Cancer Compounds.

BACKGROUND: Human cancer cell lines are valuable models for anti-cancer drug development. Although all cancer cells share common biological features, each cancer cell line has unique genotypic/ phenotypic characteristics that affect drug response. Thus, the information obtained with a specific cancer cell line cannot be easily extrapolated to other cancer cells. Consequently, cell line selection during experimental design is critical for providing proper and clinically relevant structure-activity analysis. METHODS: Herein, we critically review the use of cancer cell lines as tools for activity analysis by comparing two different scenarios: i) the use of multiple cancer cell lines, with the NCI-60 Program as the most representative example; and, ii) the selection of a single cell line with specific biological characteristics that match the rationale of compound design. RESULTS: Considering that most laboratories evaluate the activity of new compounds using few cell lines, we provide a systematic strategy for selection based on the expression levels and genetic status of the target and the effectiveness of target inhibition or silencing. We exemplify the use of public databases for data retrieval and analysis as well as the critical comparison of such information with published results. CONCLUSION: This approach refines cell line selection, avoiding the perpetuation of published poor selection and enhancing the relevance of the results.

A simultaneous determination of anti-cancer drugs in hospital effluent by DLLME HPLC-FLD, together with a risk assessment.

Currently, there is an increasing use of anti-cancer drugs, and hence their occurrence in the environment must be properly managed, in particular, in the light of their high degree of toxicity. In this study, analytical methods using HPLC-FLD assisted by microextraction and solid phase extraction, were developed and validated for the determination of doxorubicin, daunorubicin, epirubicin and irinotecan in hospital effluent. The validation results show determination coefficients (r2) higher than 0.99 and recovery values between 74% and 105%, with an intraday precision of <15%.The limit of quantification was 1.0 µg L- 1 and there were almost no matrix effects. The methods proposed were employed for the determination of the named chemotherapeutics in effluent samples of the University Hospital of Santa Maria, Brazil and quantified in the range of ≥LOQ ̶ 6.22 µg L-1. A preliminary ecotoxicological risk assessment showed values that were potentially very harmful, and thus, the treatment of the hospital effluents requires special attention.

Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading.

Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C-55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C-25°C and even after freeze-thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients.

Cancer drugs inhibit morphogenesis in the human fungal pathogen, Candida albicans

Candida infections are very common in cancer patients and it is a common practice to prescribe antifungal antibiotics along with anticancer drugs. Yeast to hyphal form switching is considered to be important in invasive candidiasis. Targeting morphogenetic switching may be useful against invasive candidiasis. In this study, we report the antimorphogenetic properties of thirty cancer drugs.

Cancer drugs inhibit morphogenesis in the human fungal pathogen, Candida albicans

Candida infections are very common in cancer patients and it is a common practice to prescribe antifungal antibiotics along with anticancer drugs. Yeast to hyphal form switching is considered to be important in invasive candidiasis. Targeting morphogenetic switching may be useful against invasive candidiasis. In this study, we report the antimorphogenetic properties of thirty cancer drugs.(AU)

Cancer drugs inhibit morphogenesis in the human fungal pathogen, Candida albicans.

Candida infections are very common in cancer patients and it is a common practice to prescribe antifungal antibiotics along with anticancer drugs. Yeast to hyphal form switching is considered to be important in invasive candidiasis. Targeting morphogenetic switching may be useful against invasive candidiasis. In this study, we report the antimorphogenetic properties of thirty cancer drugs.

Estudio de caso: estimación de los costos de la quimioterapia aplicando el protocolo completo en niños con leucemia linfoblástica aguda o con linfoma de Hodgkin / Estimation of chemotherapy costs applying the full protocol of children with acute lymphoblastic leukemia or Hodgkin's lymphoma: case study

Introducción. De todos los tipos de cáncer, la leucemia linfoblástica aguda (LLA) constituye el tipo de cáncer más común en la edad pediátrica; los linfomas ocupan el tercer lugar. El costo de los tratamientos de LLA y de linfomas de Hodgkin (LH) en niños es elevado. El objetivo de este trabajo fue calcular los costos estimados de los protocolos que utiliza el Hospital Infantil de México Federico Gómez (HIMFG) y los costos unitarios totales de los medicamentos para LLA en todas sus etapas y tipos de riesgo y para LH en sus diferentes estadificaciones. Métodos. Los cálculos se realizaron con una metodología específica utilizando los protocolos in extenso para LLA y LH, en las diferentes etapas y estadios, para un niño con peso de 20 kg y talla de 115 cm y otro con peso de 30 kg y talla de 135 cm en el HIMFG. Resultados. El costo total unitario en LLA de riesgo estándar fue de 71,655.00 MXN (~$5,430 USD) para el niño de 20 kg y de 95,825.90 MXN (~$7,260 USD) para el de 30 kg. En LH el costo del estadio IB-IIB fue de 39,342.16 MXN (~$3,000 USD) para el niño de 20 kg y de 52,620.14 MXN (~$4,000 USD) para el de 30 kg, y en el estadio III-IV correspondió a 41,469.46 MXN (~$3,150 USD) y 55,465.39 MXN (~$4,200.00), respectivamente. Conclusiones. Hubieron diferencias y ventajas del protocolo del HIMFG en LLA con respecto a otro protocolo. La comparación de los costos con otros países mostró resultados parecidos cuando solamente se evaluaron los costos unitarios.

Introduction. Of all types of cancer, acute lymphoblastic leukemia (ALL) constitutes the most common type of cancer during the pediatric age. Lymphomas occupy third place. Treatment costs of ALL and Hodgkin lymphoma (HL) in children are high. The aim of the study was to calculate total unit costs of drugs in cancer children with ALL and HL using the current protocols in the Hospital Infantil de Mexico Federico Gomez (HIMFG). The costs were estimated by risk stratification for ALL patients and according to tumor stage for HL. Methods. Calculations were performed using a specific methodology and using the complete protocols of ALL and HL in the different strata for a child weighing 20 kg with a height of 115 cm and 30 kg with a height of 135 cm. Results. The total unit cost in standard-risk ALL was 71,655.00 MXN (~$5,430 USD at the time of publication) in the patient weighing 20 kg and 95,825.90 MXN (~$7,250 USD) for the patient weighing 30 kg. In HL, the cost of stage IB-IIB was 39,342.16 MXN (~$3,000 USD) in the child weighing 20 kg and 52,620.14 MXN (~$4,000 USD) in the child weighing 30 kg. Costs for treating patient in stages III-IV corresponded to 41,469.46 MXN (~$3,150 USD) and 55,465.39 MXN (~$4,200.00), respectively. Conclusions. There were both differences and advantages in the HIMFG protocol for ALL. Comparing costs with costs in other countries showed similar results when only the unit costs were evaluated.