Ursolic acid interaction with transcription factors BRAF, V600E, and V600K: a computational approach towards new potential melanoma treatments.

CONTEXT: Melanoma is one of the cancers with the highest mortality rate for its ability to metastasize. Several targets have undergone investigation for the development of drugs against this pathology. One of the main targets is the kinase BRAF (RAF, rapidly accelerated fibrosarcoma). The most common mutation in melanoma is BRAFV600E and has been reported in 50-90% of patients with melanoma. Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ursolic acid (UA) is a pentacyclic triterpene with a privileged structure, the pentacycle scaffold, which allows to have a broad variety of biological activity; the most studied is its anticancer capacity. In this work, we reported the interaction profile of vemurafenib-OMe, dabrafenib, and UA, to define whether UA has binding capacity to BRAFWT, BRAFV600E, and BRAFV600K. Homology modeling of BRAFWT, V600E, and V600K; molecular docking; and molecular dynamics simulations were carried out and interactions and residues relevant to the binding of the inhibitors were obtained. We found that UA, like the inhibitors, presents hydrogen bond interactions, and hydrophobic interactions of van der Waals, and π-stacking with I463, Q530, C532, and F583. The ΔG of ursolic acid in complex with BRAFV600K (- 63.31 kcal/mol) is comparable to the ΔG of the selective inhibitor dabrafenib (- 63.32 kcal/mol) in complex to BRAFV600K and presents a ΔG like vemurafenib-OMe with BRAFWT and V600E. With this information, ursolic acid could be considered as a lead compound for design cycles and to optimize the binding profile and the selectivity towards mutations for the development of new selective inhibitors for BRAFV600E and V600K to new potential melanoma treatments. METHODS: The homology modeling calculations were executed on the public servers I-TASSER and ROBETTA, followed by molecular docking calculations using AutoGrid 4.2.6, AutoDockGPU 1.5.3, and AutoDockTools 1.5.6. Molecular dynamics and metadynamics simulations were performed in the Desmond module of the academic version of the Schrödinger-Maestro 2020-4 program, utilizing the OPLS-2005 force field. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

Antitumoral and Antiproliferative Potential of Synthetic Derivatives of Scorpion Peptide IsCT1 in an Oral Cavity Squamous Carcinoma Model.

The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment.

Anti-Cancer Potential of Linear ß-(1→6)-D-Glucan from Agaricus bisporus on Estrogen Receptor-Positive (ER+) Breast Cancer Cells.

Mushroom ß-D-glucans can be isolated from several species, including the widely consumed Agaricus bisporus. Besides immunomodulatory responses, some ß-D-glucans may exhibit direct antitumoral effects. It was previously observed that a ß-(1→6)-D-glucan (BDG16) has indirect cytotoxicity on triple-negative breast cancer cells. In this study, the cytotoxicity of this same glucan was observed on estrogen receptor-positive (ER+) breast cancer cells (MCF-7). Cell viability was determined by multiple methods to assess metabolic activity, lysosomal membrane integrity, and adhesion capacity. Assays to evaluate cell respiration, cell cycle, apoptosis, necroptosis, and oxidative stress were performed to determine the action of BDG16 on MCF-7 cells. A gradual and significant cell viability reduction was observed when the cells were treated with BDG16 (10-1000 µg/mL). This result could be associated with the inhibition of the basal state respiration after incubation with the ß-D-glucan. The cells showed a significant arrest in G1 phase population at 1000 µg/mL, with no induction of apoptosis. However, an increase in necrosis and necroptosis at the same concentration was observed. No difference in oxidative stress-related molecules was observed. Altogether, our findings demonstrate that BDG16 directly induces toxicity in MCF-7 cells, primarily by impairing mitochondrial respiration and promoting necroptosis. The specific mechanisms that mediate this action are being investigated.

Gut Microbiota Disruption in Hematologic Cancer Therapy: Molecular Insights and Implications for Treatment Efficacy.

Hematologic malignancies (HMs), including leukemia, lymphoma, and multiple myeloma, involve the uncontrolled proliferation of abnormal blood cells, posing significant clinical challenges due to their heterogeneity and varied treatment responses. Despite recent advancements in therapies that have improved survival rates, particularly in chronic lymphocytic leukemia and acute lymphoblastic leukemia, treatments like chemotherapy and stem cell transplantation often disrupt gut microbiota, which can negatively impact treatment outcomes and increase infection risks. This review explores the complex, bidirectional interactions between gut microbiota and cancer treatments in patients with HMs. Gut microbiota can influence drug metabolism through mechanisms such as the production of enzymes like bacterial ß-glucuronidases, which can alter drug efficacy and toxicity. Moreover, microbial metabolites like short-chain fatty acids can modulate the host immune response, enhancing treatment effectiveness. However, therapy often reduces the diversity of beneficial bacteria, such as Bifidobacterium and Faecalibacterium, while increasing pathogenic bacteria like Enterococcus and Escherichia coli. These findings highlight the critical need to preserve microbiota diversity during treatment. Future research should focus on personalized microbiome-based therapies, including probiotics, prebiotics, and fecal microbiota transplantation, to improve outcomes and quality of life for patients with hematologic malignancies.

Graphene Quantum Dots from Natural Carbon Sources for Drug and Gene Delivery in Cancer Treatment.

Cancer therapy is constantly evolving, with a growing emphasis on targeted and efficient treatment options. In this context, graphene quantum dots (GQDs) have emerged as promising agents for precise drug and gene delivery due to their unique attributes, such as high surface area, photoluminescence, up-conversion photoluminescence, and biocompatibility. GQDs can damage cancer cells and exhibit intrinsic photothermal conversion and singlet oxygen generation efficiency under specific light irradiation, enhancing their effectiveness. They serve as direct therapeutic agents and versatile drug delivery platforms capable of being easily functionalized with various targeting molecules and therapeutic agents. However, challenges such as achieving uniform size and morphology, precise bandgap engineering, and scalability, along with minimizing cytotoxicity and the environmental impact of their production, must be addressed. Additionally, there is a need for a more comprehensive understanding of cellular mechanisms and drug release processes, as well as improved purification methods. Integrating GQDs into existing drug delivery systems enhances the efficacy of traditional treatments, offering more efficient and less invasive options for cancer patients. This review highlights the transformative potential of GQDs in cancer therapy while acknowledging the challenges that researchers must overcome for broader application.

Solid Lipid Nanoparticles, an Alternative for the Treatment of Triple-Negative Breast Cancer.

Within the field of nanomedicine, which is revolutionizing cancer treatment, solid lipid nanoparticles (SLNs) have shown advantages over conventional chemotherapy when tested on cancer cells in preclinical studies. SLNs have proven to be an innovative strategy for the treatment of triple-negative breast cancer cells, providing greater efficiency than existing treatments in various studies. The encapsulation of antineoplastic drugs in SLNs has facilitated a sustained, controlled, and targeted release, which enhances therapeutic efficiency and reduces adverse effects. Moreover, the surface of SLNs can be modified to increase efficiency. For instance, the coating of these particles with polyethylene glycol (PEG) decreases their opsonization, resulting in a longer life in the circulatory system. The creation of positively charged cationic SLNs (cSLNs), achieved by the utilization of surfactants or ionic lipids with positively charged structural groups, increases their affinity for cell membranes and plasma proteins. Hyaluronic acid has been added to SLNs so that the distinct pH of tumor cells would stimulate the release of the drug and/or genetic material. The current review summarizes the recent research on SLNs, focusing on the encapsulation and transport of therapeutic agents with a cytotoxic effect on triple-negative breast cancer.

Amelioration of nephrotoxicity by targeting ferroptosis: role of NCOA4, IREB2, and SLC7a11 signaling.

Nephrotoxicity is a common complication that limits the clinical utility of cisplatin. Ferroptosis is an iron-dependent necrotic cell death program that is mediated by phospholipid peroxidation. The molecular mechanisms that disrupt iron homeostasis and lead to ferroptosis are yet to be elucidated. In this study, we aimed to investigate the involvement of nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor that mediates ferroptosis and autophagic degradation of ferritin in nephrotoxicity. Adult male Sprague-Dawley rats were randomly-assigned to four groups: control group, cisplatin (Cis)-treated group, deferiprone (DEF)-treated group, and Cis+DEF co-treated group. Serum, urine, and kidneys were isolated to perform biochemical, morphometric, and immunohistochemical analysis. Iron accumulation was found to predispose to ferroptotic damage of the renal tubular cells. Treatment with deferiprone highlights the role of ferroptosis in nephrotoxicity. Upregulation of NCOA4 in parallel with low ferritin level in renal tissue seems to participate in iron-induced ferroptosis. This study indicated that ferroptosis may participate in cisplatin-induced tubular cell death and nephrotoxicity through iron-mediated lipid peroxidation. Iron dyshomeostasis could be attributed to NCOA4-mediated ferritin degradation.

Synergistic effect of venetoclax and ibrutinib on ibrutinib-resistant ABC-type DLBCL cells.

Despite the widespread use of R-CHOP therapy in diffuse large B-cell lymphoma (DLBCL), the therapeutic efficacy for this disease remains suboptimal, primarily due to the heterogeneity of refractory and/or relapsed diseases. To address this challenge, optimization of DLBCL treatment regimens has focused on the strategy of combining an additional drug "X" with R-CHOP to enhance efficacy. However, the failure of R-CHOP combined with the BTK inhibitor ibrutinib in treating ABC-type DLBCL patients has raised significant concerns regarding ibrutinib resistance. While some studies suggest that venetoclax may synergize with ibrutinib to kill ibrutinib-resistant cells, the underlying mechanisms remain unclear. Our study aimed to validate the enhanced tumor-suppressive effect of combining ibrutinib with venetoclax against ibrutinib-resistant cells and elucidate its potential mechanisms. Our experimental results demonstrated that ibrutinib-resistant cells exhibited significant cytotoxicity to the combination therapy of ibrutinib and venetoclax, inducing cell apoptosis through activation of the mitochondrial pathway and inhibition of aerobic respiration. Furthermore, we validated the inhibitory effect of this combination therapy on tumor growth in in vivo models. Therefore, our study proposes that the combination therapy of ibrutinib and venetoclax is a promising treatment strategy that can be applied in clinical practice for ABC-type DLBCL, offering a new solution to overcome the urgent challenge of ibrutinib resistance.

Cisplatin­resistant germ cell tumor models: An exploration of the epithelial­mesenchymal transition regulator SLUG.

Germ cell tumors (GCTs) constitute diverse neoplasms arising in the gonads or extragonadal locations. Testicular GCTs (TGCTs) are the predominant solid tumors in adolescents and young men. Despite cisplatin serving as the primary therapeutic intervention for TGCTs, 10­20% of patients with advanced disease demonstrate resistance to cisplatin­based chemotherapy, and epithelial­mesenchymal transition (EMT) is a potential contributor to this resistance. EMT is regulated by various factors, including the snail family transcriptional repressor 2 (SLUG) transcriptional factor, and, to the best of our knowledge, remains unexplored within TGCTs. Therefore, the present study investigated the EMT transcription factor SLUG in TGCTs. In silico analyses were performed to investigate the expression of EMT markers in TGCTs. In addition, a cisplatin­resistant model for TGCTs was developed using the NTERA­2 cell line, and a mouse model was also established. Subsequently, EMT was assessed both in vitro and in vivo within the cisplatin­resistant models using quantitative PCR and western blot analyses. The results of the in silico analysis showed that the different histologies exhibited distinct expression profiles for EMT markers. Seminomas exhibited a lower expression of EMT markers, whereas embryonal carcinomas and mixed GCT demonstrated high expression. Notably, patients with lower SLUG expression had longer median progression­free survival (46.4 months vs. 28.0 months, P=0.022). In the in vitro analysis, EMT­associated genes [fibronectin; vimentin (VIM); actin, α2, smooth muscle; collagen type I α1; transforming growth factor­ß1; and SLUG] were upregulated in the cisplatin­resistant NTERA­2 (NTERA­2R) cell line after 72 h of cisplatin treatment. Consistent with this finding, the NTERA­2R mouse model demonstrated a significant upregulation in the expression levels of VIM and SLUG. In conclusion, the present findings suggested that SLUG may serve a crucial role in connecting EMT with the development of cisplatin resistance, and targeting SLUG may be a putative therapeutic strategy to mitigate cisplatin resistance.

In silico and in vitro study of FLT3 inhibitors and their application in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common hematological cancer in the adult population worldwide. Approximately 35% of patients with AML present internal tandem duplication (ITD) mutations in the FMS­like tyrosine kinase 3 (FLT3) receptor associated with poor prognosis, and thus, this receptor is a relevant target for potential therapeutics. Tyrosine kinase inhibitors (TKIs) are used to treat AML; however, their molecular interactions and effects on leukemic cells are poorly understood. The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild­type (WT)­FLT3 and ITD­mutated (ITD­FLT3) structural models of FLT3, in its inactive aspartic acid­phenylalanine­glycine motif (DFG­out) and active aspartic acid­phenylalanine­glycine motif (DFG­in) conformations. Furthermore, the present study evaluated the effects of the second­generation TKIs gilteritinib and quizartinib on cancer cell viability, apoptosis and proliferation in the MV4­11 (ITD­FLT3) and HL60 (WT­FLT3) AML cell lines. Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were included as an FLT3­negative group. Molecular docking analysis indicated higher affinities of second­generation TKIs for WT­FLT3/DFG­out and WT­FLT3/DFG­in compared with those of the first­generation TKIs. However, the ITD mutation changed the affinity of all TKIs. The in vitro data supported the in silico predictions: MV4­11 cells presented high selective sensibility to gilteritinib and quizartinib compared with the HL60 cells, whereas the drugs had no effect on PBMCs. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD­mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.

Modulating the phototoxicity and selectivity of a porphyrazine towards epidermal tumor cells by coordination with metal ions.

Porphyrazines (Pzs) are porphyrin derivatives that show potential application as photosensitizers for photodynamic therapy (PDT), but are still far less explored in the literature. In this work, we evaluate how the photophysics and phototoxicity of the octakis(trifluoromethylphenyl)porphyrazine (H2Pz) against tumor cells can be modulated by coordination with Mg(II), Zn(II), Cu(II) and Co(II) ions. Fluorescence and singlet oxygen quantum yields for the Pzs were measured in organic solvents and in soy phosphatidylcholine (PC) liposomes suspended in water. While H2Pz and the respective complexes with Cu(II) and Co(II) showed very low efficiency to fluoresce and to produce 1O2, the Mg(II) and Zn(II) complexes showed significantly higher quantum yields in organic solvents. The fluorescence of these two Pzs in the liposomes was sensitive to the fluidity of the membrane, showing potential use as viscosity markers. The cytotoxicity of the compounds was tested in HaCaT (normal) and A431 (tumor) cells using soy PC liposomes as drug carriers. Despite the low 1O2 quantum yields in water, the Mg(II) and Zn(II) complexes showed IC50 values against A431 cells in the nanomolar range when activated with low doses of red LED light. Their phototoxicity was ca. three times higher for the tumor cells compared to the normal ones, showing promising application as photosensitizers for PDT protocols. Considering that H2Pz and the respective Co(II) and Cu(II) complexes were practically non-phototoxic to the cells, we demonstrate the importance of the central metal ion in the modulation of the photodynamic activity of porphyrazines.

A Novel Compound from the Phenylsulfonylpiperazine Class: Evaluation of In Vitro Activity on Luminal Breast Cancer Cells.

Breast cancer (BC) is the most common cancer in women, and is characterized by its histological and molecular heterogeneity. Luminal BC is an estrogen receptor-positive subtype, with varied clinical courses. Although BC patients are eligible for hormone therapy, both early and late relapses still occur, and thus there is a demand for new cytotoxic and selective treatment strategies for these patients. In the present study, inspired by the structure of phenylsulfonylpiperazine, a series of 20 derivatives were tested in bioassays against MCF7, MDA-MB-231 and MDA-MB-453 BC cells to discover new hit compounds. After 48 h of treatment, 12 derivatives impaired cell viability and presented significant IC50 values against at least one of the tumor lineages. Overall, the luminal BC cell line MCF7 was more sensitive to treatments. Compound 3, (4-(1H-tetrazol-1-yl)phenyl)(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)methanone, was the most promising, with IC50 = 4.48 µM and selective index (SI) = 35.6 in MCF7 cells. Compound 3 also presented significant antimigratory and antiproliferative activities against luminal BC cells, possibly by affecting the expression of genes involved in the epithelial-mesenchymal transition mechanism, upregulating E-Cadherin transcripts (CDH1). Our findings suggest that phenylsulfonylpiperazine derivatives are potential candidates for the development of new therapies, especially those targeting luminal BC.

Unrevealing Lithium Repositioning in the Hallmarks of Cancer: Effects of Lithium Salts (LiCl and Li2CO3) in an In Vitro Cervical Cancer Model.

Lithium, a natural element, has been employed as a mental stabilizer in psychiatric treatments; however, some reports indicate it has an anticancer effect, prompting the consideration of repurposing lithium for cancer treatment. The potential anticancer use of lithium may depend on its form (salt type) and the type of cancer cells targeted. Little is known about the effects of Li2CO3 or LiCl on cancer cells, so we focused on exploring their effects on proliferation, apoptosis, migration, and cell cycle as part of the hallmarks of cancer. Firstly, we established the IC50 values on HeLa, SiHa, and HaCaT cells with LiCl and Li2CO3 and determined by crystal violet that cell proliferation was time-dependent in the three cell lines (IC50 values for LiCl were 23.43 mM for SiHa, 23.14 mM for HeLa, and 15.10 mM for HaCaT cells, while the IC50 values for Li2CO3 were 20.57 mM for SiHa, 11.52 mM for HeLa, and 10.52 mM for HaCaT cells.) Our findings indicate that Li2CO3 and LiCl induce DNA fragmentation and caspase-independent apoptosis, as shown by TUNEL, Western Blot, and Annexin V/IP assay by flow cytometry. Also, cell cycle analysis showed that LiCl and Li2CO3 arrested the cervical cancer cells at the G1 phase. Moreover, lithium salts displayed an anti-migratory effect on the three cell lines observed by the wound-healing assay. All these findings imply the viable anticancer effect of lithium salts by targeting several of the hallmarks of cancer.

Antineoplastic Activity of Sodium Caseinate in a Cytarabine-Resistant Mouse Acute Myeloid Leukemia Cell Line.

BACKGROUND: Acute myeloid leukemia (AML) is a hematological neoplasm of rapid and progressive onset, and is the most common form of leukemia in adults. Chemoresistance to conventional treatments such as cytarabine (Ara-C) and daunorubicin is a main cause of relapse, recurrence, metastasis, and high mortality in AML patients. It is known that sodium caseinate (SC), a salt derived from casein, a milk protein, inhibits growth and induces apoptosis in acute myeloid leukemia cells but not in normal hematopoietic cells. However, it is unknown whether SC retains its antileukemic effect in cytarabine-resistant AML cell lines. OBJECTIVE: To evaluate the antineoplastic effect of SC in cytarabine-resistant leukemia models. METHODS: The SC inhibits the growth and induces apoptosis in parental WEHI-3 AML cells. Here, we generated two cytarabine-resistant sublines, WEHI-CR25 and WEHI-CR50, which exhibit 6- and 16-fold increased resistance to cytarabine, respectively, compared to the parental WEHI-3 cells. Thus, these sublines mimic a chemoresistant model. RESULTS: We demonstrate that WEHI-CR25 and WEHI-CR50 cells retain sensitivity to SC, similar to parental WEHI-3 cells. This sensitivity results in inhibited cell proliferation, induced apoptosis, and increased expression of ENT1 and dCK, molecules involved in the entry and metabolism of Ara-C, while decreasing MDR1 expression. Additionally, we observed that SC prolonged the survival of WEHI-CR50 tumor-bearing mice, despite their resistance to Ara-C. CONCLUSION: This is the first evidence that SC, a milk protein, may inhibit proliferation and induce apoptosis in cytarabine-resistant cells.

Olive Leaves as a Source of Anticancer Compounds: In Vitro Evidence and Mechanisms.

Olive trees not only produce olives but also generate a substantial amount of waste and by-products, including leaves, pomace (the solid remains after pressing olives for oil), and wastewater from the olive oil-making process. The waste products, particularly the leaves, contain bioactive compounds, especially phenolic compounds, known for their health benefits, such as high antioxidant potential and the ability to reduce inflammation. These compounds have shown promise in preventing and treating cancer. This review, based on in vitro evidence, provides a detailed description and discussion of the mechanisms through which these compounds from olive leaves can prevent development, the ways they might act against cancer cells, and their potential to increase the sensitivity of tumor cells to conventional anticancer therapy. The possible synergistic effects of these compounds suggest that olive leaf extracts may offer a promising approach for cancer treatment, compared with isolated compounds, thus providing novel possibilities for cancer therapy.

Honey and Aloe vera Solution Increases Survival and Modulates the Tumor Size In Vivo.

SCOPE: The combination of honey and Aloe vera is used as a popular complementary treatment for cancer due to their nutraceutical properties. This study aims to investigate the anticancer activity of honey and A. vera solution and its ethanolic extraction through in vitro and in vivo approaches. METHODS AND RESULTS: After comparisons of honey and A. vera (HA) solution and its ethanolic extraction solution (E) samples by UPLC-ESI-MS/MS, the study verifies HA-treatment affected only Walker tumor cells viability at the highest dose, and E-treatment has a more cytotoxic/antiproliferative effect in MCF-7 and Walker-256 cells. The in vivo results show a higher survival rate in Walker-256 tumor-bearing rats (WHA), with higher NK cell infiltration in tumor tissue and a tendency in the WE group. These results are possible due to decreased mannose-based immunomodulatory polysaccharides and aloin-A contents in the ethanolic extract solution compared to HA solution. CONCLUSION: The current study provides compelling evidence of selectively cytotoxic against tumor cells under honey and A. vera solution and ethanolic extraction solution treatment, due to the cytotoxic/antiproliferative compounds. Therefore, the use of honey and A. vera solution could be used as a basis for coadjuvant therapy in cancer treatment.

Effects of Arborvitae (Thuja plicata) Essential Oil on Cervical Cancer Cells: Insights into Molecular Mechanisms.

AIMS: This study aimed to assess the effects of AEO in an in vitro model of cell lines derived from cervical cancer-namely, HeLa and SiHa-by screening for AEO's cytotoxic properties and examining its influence on the modulation of gene expression. BACKGROUND: Cervical cancer stands as a prevalent global health concern, affecting millions of women worldwide. The current treatment modalities encompass surgery, radiation, and chemotherapy, but significant limitations and adverse effects constrain their effectiveness. Therefore, exploring novel treatments that offer enhanced efficacy and reduced side effects is imperative. Arborvitae essential oil, extracted from Thuja Plicata, has garnered attention for its antimicrobial, anti-inflammatory, immunomodulatory, and tissue-remodeling properties; however, its potential in treating cervical cancer remains uncharted. OBJECTIVE: The objective of this study was to delve into the molecular mechanisms induced by arborvitae essential oil in order to learn about its anticancer effects on cervical cancer cell lines. METHODS: The methods used in this study were assessments of cell viability using WST-1 and annexin V- propidium iodide, mRNA sequencing, and subsequent bioinformatics analysis. RESULTS: The findings unveiled a dose-dependent cytotoxic effect of arborvitae essential oil on both HeLa and SiHa cell lines. Minor effects were observed only at very low doses in the HaCaT non-tumorigenic human keratinocyte cells. RNA-Seq bioinformatics analysis revealed the regulatory impact of arborvitae essential oil on genes enriched in the following pathways: proteasome, adherens junctions, nucleocytoplasmic transport, cell cycle, proteoglycans in cancer, protein processing in the endoplasmic reticulum, ribosome, spliceosome, mitophagy, cellular senescence, and viral carcinogenesis, among others, in both cell lines. It is worth noting that the ribosome and spliceosome KEGG pathways are the most significantly enriched pathways in HeLa and SiHa cells. CONCLUSION: Arborvitae essential oil shows potential as a cytotoxic and antiproliferative agent against cervical cancer cells, exerting its cytotoxic properties by regulating many KEGG pathways.

Graphitic carbon nitride as a novel anticancer agent: potential mechanisms and efficacy in prostate cancer and glioblastoma treatment.

Carbon-derived compounds are gaining traction in the scientific community because of their unique properties, such as conductivity and strength, and promising innovations in technology and medicine. Graphitic nitride carbon (g-C3N4) stands out among these compounds because of its potential in antitumor therapies. This study aimed to assess g-C3N4's antitumor potential and cytotoxic mechanisms. Prostate cancer (DU-145) and glioblastoma (U87) cell lines were used to evaluate antitumor effects, whereas RAW 264.7 and HFF-1 non-tumor cells were used for selectivity evaluation. The synthesized g-C3N4 particles underwent comprehensive characterization, including the assessment of particle size, morphology, and oxygen content, employing various techniques, such as X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy, and atomic force microscopy. The results indicated that g-C3N4 significantly affected tumor cell proliferation and viability, exhibiting high cytotoxicity within 48 h. In non-tumor cells, minimal effects on proliferation were observed, except for damage to the cell membranes of RAW 264.7 cells. Moreover, g-C3N4 changed the cell morphology and ultrastructure, affecting cell migration in U87 cells and potentially enhancing migration in RAW 264.7 cells. Biochemical assays in Balb/C mice revealed alterations in alanine aminotransferase, aspartate aminotransferase, and amylase levels. In conclusion, g-C3N4 demonstrated promising antitumor effects with minimal toxicity to non-tumor cells, suggesting its potential in neoplasm treatment.

High-intensity interval training alleviates liver inflammation by regulating the TLR4/NF-κB signaling pathway and M1/M2 macrophage balance in female rats with cisplatin hepatotoxicity.

Cisplatin (CDDP) is an antineoplastic drug whose adverse effects include hepatotoxicity. The inflammatory process is crucial in the progression of liver injuries. Exercise is known for its anti-inflammatory effects, but the influence of different training modalities on hepatoprotection is still unclear. This study aims to compare the impacts between preconditioning with high-intensity interval training (HIIT) and traditional continuous training of low (LT) and moderate (MT) intensities on inflammatory markers in Wistar female rats with CDDP-induced hepatotoxicity. Thirty-five rats were divided into five groups: control and sedentary (C + Sed), treated with CDDP and sedentary (CDDP + Sed), treated with CDDP and subjected to LT (CDDP + LT), treated with CDDP and subjected to MT (CDDP + MT), and treated with CDDP and subjected to HIIT (CDDP + HIIT). The training protocols consisted of treadmill running for 8 weeks before CDDP treatment. The rats were euthanized 7 days after the treatment. Liver samples were collected to evaluate the expression of various inflammatory markers and types of macrophages. Our results indicated that HIIT was the only protocol to prevent the increase in all analyzed pro-inflammatory cytokines and reduce the number of ED-1-positive cells, attenuating the TLR4/NF-κB signaling pathway in the liver. Additionally, HIIT increased the anti-inflammatory cytokine IL-10 and regulated M1/M2 macrophage polarization. Thus, this study suggests that preconditioning with HIIT is more effective in promoting hepatoprotective effects than LT and MT, regulating inflammatory markers through modulation of the TLR4/NF-κB signaling pathway and M2 macrophage polarization in the hepatic tissue of female rats treated with CDDP.

5-nitro-thiophene-thiosemicarbazone derivative induces cell death, cell cycle arrest, and phospho-kinase shutdown in pancreatic ductal adenocarcinoma cells.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. This study explores the potential of novel 5-nitro-thiophene-thiosemicarbazone derivatives as therapeutic agents for PDAC. METHODS: We evaluated the cytotoxicity of seven derivatives in peripheral blood mononuclear cells (PBMCs) and PDAC cell lines. Promising candidates (PR12 and PR17) were further analyzed for their effects on colony formation, cell cycle progression, and reactive oxygen species (ROS) production. PR17, the most promising derivative, was subjected to additional investigation, including analysis of autophagy-related genes and protein kinase inhibition. RESULTS: Three derivatives (PR16, PR19, and PR20) displayed cytotoxicity towards PBMCs. PR12 reduced colony formation and G0/G1 cell cycle arrest in PDAC cells. Notably, PR17 exhibited potent activity in MIA PaCa-2 cells, inducing S-phase cell cycle arrest, downregulating autophagy genes, and inhibiting key protein kinases. CONCLUSION: PR17, a 5-nitro-thiophene-thiosemicarbazone derivative, demonstrates promising antineoplastic activity against PDAC cells by potentially modulating cell cycle progression, autophagy, and protein kinase signaling. Further studies are warranted to elucidate the detailed mechanism of action and explore its efficacy in vivo.