Standard Chemotherapeutic Drugs Research Articles

Design of an innovative aptasensor for the detection of chemotherapeutic drug Fludarabine phosphate

Monitoring the concentration of Fludarabine phosphate, a standard chemotherapeutic drug widely used in cancer treatment, is vital for ensuring the drug’s safety and effectiveness, tailoring treatments to individual needs, and consequently improving overall patient outcomes. Regarding the limitations of conventional techniques in terms of complexity, large time measurements, and a high cost, there is an urgent need to develop simple, rapid, and cost-effective devices. In this paper, we report the design of an aptasensor for the specific and selective detection of Fludarabine. Systematic evolution of ligands by exponential enrichment (SELEX) protocol was performed to select a specific aptamer for Fludarabine. Eleven rounds were carried out, and nine sequences were selected. Based on the dissociation constant (Kd), Ful-3, exhibiting the highest affinity (18.86 nM), was chosen and integrated into a simple electrochemical aptasensing platform for Fludarabine detection. Electrochemical results demonstrated good performance of the selected aptamer in detecting Fludarabine within the analytical range of 1 to 150 pg/mL and with LOD and LOQ in the order of 0.11 pg/mL (0.31 fM) and 0.39 pg/mL (1.06 fM), respectively. The developed platform also showed good selectivity against different analogous molecules and high applicability in serum-spiked samples, with recovery percentages ranging from 96.81 to 99.04%. Considering the encouraging results, this research presents an excellent alternative in terms of simplicity, stability, ease of use, reduction of sample volume, and low cost.

Gold(I) complexes of the type [AuL{κC-2-C6H4P(S)Ph2}] [L = PTA, PPh3, PPh2(C6H4-3-SO3Na) and PPh2(2-py)]: Synthesis, characterisation, crystal structures, and In Vitro and In Vivo anticancer properties

Four new mononuclear gold (I) compounds of the type [AuL{κC-2-C6H4P(S)Ph2}] {L = PTA (1), PPh3 (2), PPh2(C6H4-3-SO3Na) (3), and PPh2(2-py) (4)} were prepared by scission of the dinuclear compound [Au2{μ-2-C6H4P(S)Ph2}2] by L or via a transmetalation reaction using the organotin reagent 2-Me3SnC6H4P(S)Ph2 and a suitable gold halide precursor. The cytotoxic potential of complexes 1–4 was evaluated against four human cancer cell lines of diverse cellular origin: cervical (HeLa), prostate (PC-3), non-small cell lung adenocarcinoma (A549), and fibrosarcoma (HT-1080). The in vitro cytotoxicity results showed that 1 demonstrated exceptional anticancer activity with IC50 values ranging from 0.08 to 3.5 μM. Complex 3, which contains a sulfonated triphenyl phosphine ligand, displayed the weakest anticancer activity with IC50 values ranging from 3.1 to >50 μM. When compared to the standard chemotherapeutic drug cisplatin, 1 displayed approximately 27-fold greater cytotoxic activity against cervical cancer cells and 3.5- and 7.5-fold greater activities against prostate and fibrosarcoma cancer cells, respectively. Additionally, 1 exhibited 3-fold selectivity for cervical cancer cells compared to non-cancerous HEK-293 cells. Mechanistic investigations revealed that 1 induced apoptosis, which was associated with elevated reactive oxygen species (ROS) and inhibition of the intracellular enzyme thioredoxin reductase. Furthermore, 1 exhibited notable antiangiogenic characteristics in an in vivo model using transgenic zebrafish Tg(fli1a:EGFP). In vivo studies using mouse xenograft models showed that complex 1 displayed superior inhibition of tumour growth (82 %) compared to the clinical drug cisplatin (29 %). Overall, these results highlight the potential of gold (I) compounds as novel antitumour agents.

In vitro, bioassay guided identification of anticancer compounds from Vitex negundo Linn. Leaf using T98 glioma cells

Gliomas, the most devastating of brain tumours, pose immense therapeutic challenges due to the adverse effects of standard chemotherapeutic drugs. Seeking alternatives, natural products have emerged as promising sources for cancer treatment. Vitex negundo, a significant medicinal plant in traditional medicine, offers potential remedies for various ailments. In this study, fractionation via column chromatography we isolated fraction #25 from leaves of Vitex negundo. Employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, wound healing assay, flow cytometry for cell cycle analysis, and HRLC-MS for compound identification, we investigated its effects on glioma cells. Results indicate that fraction #25 significantly reduces glioma cell viability and proliferation, inhibits cell migration in a dose-dependent manner, and arrests the cell cycle at G1 phase. Compound analysis reveals the presence of potent antiproliferative agents, including 7-hydroxy-3,4,5,6,8-pentamethoxyflavone, Virol-B, Momordin Ia, and Oryzalexin A. These findings underscore the potential of Vitex negundo as a source of anticancer compounds against glioma cells.

Impact of V9302, a Competitive Antagonist of Transmembrane Glutamine Flux on Reversal of Resistance in Breast Cancer Cell Lines.

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present study aimed to investigate the in vitro effects of V9302, a competitive antagonist of glutamine flux, on different subtypes of breast cancers (estrogen, progesterone, and HER2 receptor-positive or negative, and Pgp-negative and Pgp-overexpressing). The interactions of V9302 with standard chemotherapeutic drugs (doxorubicin and cisplatin) were also determined by MTT staining on breast cancer cell lines. Furthermore, the influence of V9302 on the cell cycle of MCF-7 and its Pgp-overexpressing counterpart KCR was monitored by flow cytometry. It was shown that V9302 exerted synergistic interactions with doxorubicin in all breast cancer cell lines. In cell cycle analysis, the KCR cell line was more sensitive to V9302. After 48 h, cell proliferation was completely blocked, and elevated G1, suppressed S, and decreased G2/M could be detected. Inhibition of glutamate transport can be assumed to block resistance related to Pgp.

Antioxidant and cytotoxic activities of protein hydrolysates from shrimp shell wastes, germinated soybean and pigeon pea flour blends: A mixture response surface methodology approach

Cancer has high prevalence rate and mortality with conventional chemotherapy and other management protocols being both expensive and inaccessible especially in low/medium income countries (LMIC). Sourcing alternative cheaper and easily accessible treatment from blends of antioxidants sources can reduce the burden of cancer on patients. This work therefore seeks to produce a blend from the protein hydrolysates of shrimp shell waste, germinated soybean and germinated pigeon pea which not only has high antioxidant activity but also can inhibit cervical cancer cell proliferation. In vitro antioxidant and cytotoxic activities of the mixtures of germinated pigeon pea, germinated soybean, and shrimp shell waste hydrolysates were evaluated using the mixture response surface methodology (MRSM). Fourteen blends were obtained using the simplex centroid design. Total phenolic content (TPC), 2, 2-Diphenyl-1-Picrylhydrazyl (DPPH) and % cytotoxicity of the samples were analysed. Numerical optimization was conducted with the goal of simultaneously maximizing the DPPH scavenging activity and TPC while minimizing % cytotoxicity. The optimized blend consisted of 91.06 % pigeon pea, 8.94 % shrimp shell waste and 0 % soybean. The predicted responses obtained were 74.28 % DPPH scavenging activity, 39.6 GAE mg/dL TPC and 21 % cytotoxicity. The IC50 values for the optimized blend and a standard chemotherapeutic drug were 0.260 mmol/mL and 0.013 mmol / mL respectively. This in vitro study revealed that the pigeon pea - shrimp shell waste blend, as generated by MRSM, was comparable to a standard anticarcinogenic drug with respect to potency. Keywords: pigeon pea, soybean, hydrolysates, shrimp shell waste, cytotoxicity, antioxidants, DPPH

HMGN1 loss sensitizes lung cancer cells to chemotherapy

The high mobility group nucleosome binding (HMGN) family, constitutes a large family of non-histone protein family known to bind the acidic patch of the nucleosomes with various key cellular functions. Several studies have highlighted the pivotal roles of HMGNs in the pathogenic process of various cancer types. However, the roles of HMGN family in lung adenocarcinoma (LUAD) have not been fully elucidated. Herein, integrative analyses of multiple-omics data revealed that HMGNs frequently exhibit dysregulation in LUAD. Subsequent analysis of the clinical relevance of HMGN1 demonstrated its association with poor prognosis in LUAD and its potential as a diagnostic marker to differentiate LUAD from healthy controls. Additionally, functional enrichment analysis suggested that HMGN1 was mainly involved in DNA repair. To corroborate these findings, cellular experiments were conducted, confirming HMGN1’s crucial involvement in homologous recombination repair and its potential to enhance the sensitivity of LUAD cells to standard chemotherapeutic drugs. This study proposes HMGN1 as a novel prognostic biomarker and a promising target for chemotherapy in lung adenocarcinoma.

Abstract 4608: Combinations of Cdc-like kinase (CLK) inhibitors with targeted oncology agents or standard chemotherapy in patient-derived multi-cell type tumor spheroids

Abstract The alternative splicing of mRNA precursors allows one gene the capacity to yield multiple protein isoforms, each with distinct functions. Although this intricate process is subject to stringent regulation under normal physiological conditions, aberrant alternative splicing can generate atypical proteins and contribute to various diseases, including cancer. By activating splicing factors, Cdc-like kinases (CLKs) serve as pivotal regulators of alternative splicing and are considered promising therapeutic targets for various tumors. In this study, we investigated the activity of two CLK inhibitors, cirtuvivint (SM08502) and CC-671, in combination with precision oncology agents or conventional chemotherapeutics. Thirty highly characterized patient-derived cancer cell lines were selected from the National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov/models/database.htm). The cell lines were derived from a range of cancer types including head and neck, bladder, pancreas, endometrial, colon, and melanoma, and contained clinically relevant variants of KRAS (G12C, G12D). Multi-cell type tumor spheroids were grown from a ratio of 6:2.5:1.5 malignant cells, endothelial cells, and mesenchymal stem cells, respectively. Following three days of growth, the spheroids were treated with single agents or combinations at concentrations up to their clinical Cmax value, if reported. After seven days of continuous drug exposure, cell viability was assessed using the CellTiter-Glo 3D assay. As a single agent, cirtuvivint showed concentration-dependent activity in all spheroid types with 1 – 3 logs of cytotoxicity, whereas CC-671 did not show activity in all spheroid types and achieved no more than 1 log of cytotoxicity. Among the standard chemotherapeutic drugs, doxorubicin and SN-38 demonstrated additive and greater-than-additive cytotoxicity in various spheroid types when combined with either CLK inhibitor. Several of the targeted oncology drugs exhibited noteworthy additive and greater-than-additive cytotoxicity when combined with a CLK inhibitor. These agents included the XPO1 inhibitor, eltanexor, the MCL-1 inhibitor, tapotoclax, the α-isoform-specific PI3K inhibitor, inavolisib, and the pan-PI3K inhibitor, copanlisib. Notably, combinations of the CLK inhibitors with the KRAS G12D variant-specific inhibitor, MRTX-1133, showed selective activity against all tumor cell lines harboring this genetic variant. Interestingly, a strong antagonistic interaction between paclitaxel and CC-671 was observed in all thirty spheroid types, while no such interaction was observed with cirtuvivint. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Thomas Steven Dexheimer, Thomas Silvers, Nathan P. Coussens, Steven D. Gore, James H. Doroshow, Beverly A. Teicher. Combinations of Cdc-like kinase (CLK) inhibitors with targeted oncology agents or standard chemotherapy in patient-derived multi-cell type tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4608.

The postbiotic sodium butyrate synergizes the antiproliferative effects of dexamethasone against the AGS gastric adenocarcinoma cells.

A growing body of literature underlines the fundamental role of gut microbiota in the occurrence, treatment, and prognosis of cancer. In particular, the activity of gut microbial metabolites (also known as postbiotics) against different cancer types has been recently reported in several studies. However, their in-depth molecular mechanisms of action and potential interactions with standard chemotherapeutic drugs remain to be fully understood. This research investigates the antiproliferative activities of postbiotics- short-chain fatty acid (SCFA) salts, specifically magnesium acetate (MgA), sodium propionate (NaP), and sodium butyrate (NaB), against the AGS gastric adenocarcinoma cells. Furthermore, the potential synergistic interactions between the most active SCFA salt-NaB and the standard drug dexamethasone (Dex) were explored using the combination index model. The molecular mechanisms of the synergy were investigated using reactive oxygen species (ROS), flow cytometry and biochemometric and liquid chromatography-mass spectrometry (LC-MS)-driven proteomics analyses. NaB exhibited the most significant inhibitory effect (p < 0.05) among the tested SCFA salts against the AGS gastric cancer cells. Additionally, Dex and NaB exhibited strong synergy at a 2:8 ratio (40 μg/mL Dex + 2,400 μg/mL NaB) with significantly greater inhibitory activity (p < 0.05) compared to the mono treatments against the AGS gastric cancer cells. MgA and NaP reduced ROS production, while NaB exhibited pro-oxidative properties. Dex displayed antioxidative effects, and the combination of Dex and NaB (2,8) demonstrated a unique pattern, potentially counteracting the pro-oxidative effects of NaB, highlighting an interaction. Dex and NaB individually and in combination (Dex:NaB 40:2400 μg/mL) induced significant changes in cell populations, suggesting a shift toward apoptosis (p < 0.0001). Analysis of dysregulated proteins in the AGS cells treated with the synergistic combination revealed notable downregulation of the oncogene TNS4, suggesting a potential mechanism for the observed antiproliferative effects. These findings propose the potential implementation of NaB as an adjuvant therapy with Dex. Further investigations into additional combination therapies, in-depth studies of the molecular mechanisms, and in vivo research will provide deeper insights into the use of these postbiotics in cancer, particularly in gastric malignancies.

Abstract A066: The cytotoxic effects of oxaliplatin and 5-fluorouracil against low-grade serous ovarian cancer cells

Abstract A066: The cytotoxic effects of oxaliplatin and 5-fluorouracil against low-grade serous ovarian cancer cells

Artesunate-loaded solid lipid nanoparticles resist esophageal squamous cell carcinoma by inducing Ferroptosis through inhibiting the AKT/mTOR signaling

Esophageal squamous cell carcinoma (ESCC) is a severe malignancy with high incidence and mortality rate in China, while the application of standard chemotherapeutic drugs for ESCC meets the barriers of high toxicity and multiple drug resistance (MDR). In recent years, the anticancer effects of artesunate (ART), a Chinese medicine monomer have gained extensive attentions due to its characteristics of low toxicity, high potency, and reversal of MDR. In this study, we develop the artesunate-loaded solid lipid nanoparticles (SLNART) to overcome the poor water solubility and bioavailability of ART, further improving the efficiency of ART on ESCC treatment. Especially mentioned, SLNART is shown to present marked inhibitory effects on ESCC development based on the induction of ferroptosis by two pathways included upregulating TFR to increase Fe2+ ions and inhibiting the AKT/mTOR signaling to downregulate GPX4. Collectively, this study is the first to pave a promising approach for ESCC therapy based on a strategy of developing SLNART to induce ferroptosis by mediating Fe2+ ions and AKT/mTOR signaling.

Management challenges for Gestational Trophoblastic Neoplasia in a 54 years old perimenopausal woman ; A case report.

Background: Gestational trophoblastic diseases (GTD) are pregnancy-related disorders that originate from trophoblast cells. They include benign and aggressive tumors, such as invasive moles, choriocarcinomas, placental site trophoblastic tumors, and epithelioid trophoblastic tumors. Gestational trophoblastic neoplasia (GTN) mostly occur in women of reproductive age, whereas it is extremely rare in postmenopausal women. Case presentation: A 54-year-old woman presented with prolonged bleeding, abdominal fullness, and pelvic mass with a history of a missed abortion two months prior to the onset of the symptoms and was medically managed. Her general and systemic examination findings were unremarkable. On abdominal examination, the uterus was 14 weeks in size. On speculum examination, the cervix and vagina were normal. On bimanual examination, the uterus was 14 weeks, mobile, and the adnexa were normal. Investigations included serum beta-human chorionic gonadotropin (hCG), abdominopelvic magnetic resonance imaging, and chest computed tomography. Her initial hCG was 179,000 mIu/ml with a bulky uterus and endometrial mass of approximately 6 cm and multiple bilateral chest metastatic nodules. The patient was scored as stage III:10 and started on etoposide, methotrexate, actinomycin alternating with cyclophosphamide, and vincristine (EMACO). She received 11 cycles of EMACO. Her management included repeated transfusions, granulocyte-stimulating factors administration, and ICU admission. Discussion: Gestational trophoblastic neoplasia accounts for rare gynecological malignancies in postmenopausal women. The risk of GTD progressing to GTN is 5% in younger women and five-fold higher (27%) after 45 years. Conclusion: GTN is a rare gynecological malignancy in postmenopausal women. The presentation mimics other gynecological malignancies. Hence, a high index of suspicion is required. Histopathological confirmation is mostly unavailable. It carries a poor prognosis compared with younger women with a high incidence of metastatic, recurrent, and low tolerance to standard multi-agent chemotherapeutic drugs.

Cytotoxic activity of isoquinoline alkaloids and herbal extracts from selected plants against human cancer cell lines: harnessing the research potential in cancer drug discovery with modern scientific trends and technology.

The increasing prevalence of cancer has led to a growing interest in alternative medicine methods and treatments. This study aimed to assess the cytotoxicity of isoquinoline alkaloids and herbal extracts from selected plants against human cancer cell lines, including melanoma and squamous cell carcinoma. The investigation involved in vitro cell viability assays using various cancer cell lines and normal skin fibroblasts as control cells. Additionally, a zebrafish model was employed for in vivo evaluation of cytotoxic activity. The results indicated that the tested alkaloids and extracts exhibited promising cytotoxic effects, showing higher potency than standard chemotherapeutic drugs. In comparison, these findings support the exploration of isoquinoline alkaloids and herbal extracts as potential candidates for developing novel anti-melanoma and anti-squamous cell carcinoma drugs. The primary inclusion criterion that was taken into consideration in this study effort was the therapeutic application of the cytotoxic effects of specific plant-based pharmacological components or chemicals produced from herbal extracts that are ordinarily cytotoxic.

MiR-548c-3p through suppressing Tyms and Abcg2 increases the sensitivity of colorectal cancer cells to 5-fluorouracil

BackgroundColorectal cancer, is one of most prevalent the cancer in the world. 5-Fluorouracil is a standard chemotherapeutic drug while the acquisition of resistance to 5-Fluorouracil is one of the problems during treatment. In this study, we aimed to find the miRNAs that modulate the expression of Tyms and Abcg2 as resistance-inducing genes in the resistant cell lines to 5-Fluorouracil. Methods5-Fluorouracil-resistant HCT116 and SW480 cell lines were generated by consecutive treatment of cells with 5-Fluorouracil. This resistance induction was validated by MTT assays. The expression of the Tyms and Abcg2 gene and miR-548c-3p were studied by quantitative real-time PCR in the cell lines. ResultsWe hypothesized that miR-548c-3p is targeting Tyms and Abcg2 simultaneously. Increased expression Tyms gene in the two most resistant cell lines derived from HCT116 and all resistant cell lines derived from SW480 except one were seen. Increased expression of Abcg2 was observed in the most resistant HCT116-derived cell line and all resistant cell lines, derived from SW480. In all resistant cell lines, the expression of miR-548c-3p was decreased. ConclusionIt can be concluded downregulation of miR548c-3p is in line with Tyms and Abcg2 overexpression in resistant cell lines to 5-Fluorouracil.

A Polyherbal Ashwagandha Formulation Exhibits Adjunctive Antitumor Efficacy Against U266 Myeloma Cells by Multi-Strategic Cytotoxic Effects: An Experimental Approach.

The present study explored the molecular mechanism of herbal (Unani) drug Habb-e-asgandh as anti-tumorigenic adjuvant therapy experimentally in U266 cells and its role in treatment of Multiple myeloma. The formulation of Habb-e-asgandh is investigated alone or as a combinatorial therapy with standard drug lenalidomide to check for its efficacy against U266 myeloma cells for prevention of drug relapse and resistance. We performed the following assays on singly or in combination of Habb-e-asgandh-Lenalidomide treated U266 cells. The cytotoxicity evaluation done by MTT assay, we studied cell cycle kinetics by Propidium Iodide staining, mitochondrial apoptosis analysis by Annexin V/PI dual staining and JC1 staining assays. Further, anti-oxidative potential was assessed by ORAC assay and cytokine levels estimation of anti-inflammatory (TNF-alpha and IL6) and anti-angiogenic (VEGF and Ang-2) markers were done by ELISA. The myeloma U266 cells when treated with Habb-e-asgandh alone or in combination with standard drug lenalidomide showed cytotoxicity in dose dependent manner with promising effects at 0.4 mg/ml (IC30) and 1.5 mg/ml (IC50) inhibitory concentrations. The formulation treated cells showed modulation in cell cycle kinetics patterned by sub Go/G1 population accumulation. Furthermore, it induced mitochondrial apoptosis mainly at half maximal inhibitory concentration and in combinatorial combinations. Significantly elevated oxidative capacities (p<0.05) and reduced levels of angiogenic and pro-inflammatory markers were observed. Multiple mechanism based inhibition by Habb-e-asgandh in co-treatment with lenalidomide against myeloma cells is indicated. Conclusion: Habb-e-asgandh formulation possess anti-tumorigenic efficacy against multiple myeloma. The adjunctive Habb-e-asgandh formulation with standard chemotherapeutic drug may prove to be a potent anti-myeloma agent in interventional therapy for Multiple myeloma if further studied in future avenues.

Therapeutic Potential of 1,8-Dihydroanthraquinone Derivatives for Breast Cancer.

Breast cancer (BC) is the most common malignancy among women worldwide. In recent years, significant progress has been made in BC therapy. However, serious side effects resulting from the use of standard chemotherapeutic drugs, as well as the phenomenon of multidrug resistance (MDR), limit the effectiveness of approved therapies. Advanced research in the BC area is necessary to create more effective and safer forms of therapy to improve the outlook for individuals diagnosed with this aggressive neoplasm. For decades, plants and natural products with anticancer properties have been successfully utilized in treating various medical conditions. Anthraquinone derivatives are tricyclic secondary metabolites of natural origin that have been identified in plants, lichens, and fungi. They represent a few botanical families, e.g., Rhamnaceae, Rubiaceae, Fabaceae, Polygonaceae, and others. The review comprehensively covers and analyzes the most recent advances in the anticancer activity of 1,8-dihydroanthraquinone derivatives (emodin, aloe-emodin, hypericin, chrysophanol, rhein, and physcion) applied both individually, or in combination with other chemotherapeutic agents, in in vitro and in vivo BC models. The application of nanoparticles for in vitro and in vivo evidence in the context of 1,8-dihydroanthraquinone derivatives was also described.

The Role of the Microenvironment and Cell Adhesion Molecules in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy whose progression largely depends on the lymph node and bone marrow microenvironment. Indeed, CLL cells actively proliferate in specific regions of these anatomical compartments, known as proliferation centers, while being quiescent in the blood stream. Hence, CLL cell adhesion and migration into these protective niches are critical for CLL pathophysiology. CLL cells are lodged in their microenvironment through a series of molecular interactions that are mediated by cellular adhesion molecules and their counter receptors. The importance of these adhesion molecules in the clinic is demonstrated by the correlation between the expression levels of some of them, in particular CD49d, and the prognostic likelihood. Furthermore, novel therapeutic agents, such as ibrutinib, impair the functions of these adhesion molecules, leading to an egress of CLL cells from the lymph nodes and bone marrow into the circulation together with an inhibition of homing into these survival niches, thereby preventing disease progression. Several adhesion molecules have been shown to participate in CLL adhesion and migration. Their importance also stems from the observation that they are involved in promoting, directly or indirectly, survival signals that sustain CLL proliferation and limit the efficacy of standard and novel chemotherapeutic drugs, a process known as cell adhesion-mediated drug resistance. In this respect, many studies have elucidated the molecular mechanisms underlying cell adhesion-mediated drug resistance, which have highlighted different signaling pathways that may represent potential therapeutic targets. Here, we review the role of the microenvironment and the adhesion molecules that have been shown to be important in CLL and their impact on transendothelial migration and cell-mediated drug resistance. We also discuss how novel therapeutic compounds modulate the function of this important class of molecules.

Targeting the mitochondrial calcium uniporter inhibits cancer progression and alleviates cisplatin resistance in esophageal squamous cell carcinoma.

Cisplatin is the standard chemotherapeutic drug used for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired cisplatin resistance is the primary obstacle to prolonging patient survival time. Here, the therapeutic effects of mitochondrial calcium uniporter (MCU) inhibition on tumor growth and cisplatin resistance in ESCC were assessed. MCU was stably overexpressed or knocked down in three ESCC cell lines and three cisplatin‑resistant ESCC cell lines. Then, proliferation, migration, and mitochondrial membrane potential (MMP) were measured by colony formation, wound healing, Transwell, and JC‑1 staining assays. MCU, MICU2, MICU1, and PD‑L1 levels were detected through western blotting and immunofluorescence. ESCC and cisplatin‑resistant ESCC xenograft mouse models were established. After MCU knockdown, tumor volume was measured. The expression levels of proliferation markers (CyclinD1 and Ki‑67), MICU1/2, PD‑L1, epithelial-mesenchymal transition (EMT) markers (vimentin, β‑catenin, and E‑cadherin), and the angiogenesis marker CD34 were detected through western blotting, immunohistochemistry, or immunofluorescence. The results showed that MCU overexpression significantly promoted proliferation, migration, and MMP in ESCC cells and cisplatin‑resistant ESCC cells. However, proliferation, migration, and MMP were suppressed following MCU knockdown. In ESCC cells, MCU overexpression markedly increased MICU2, MICU1, and PD‑L1 levels, and the opposite results were observed when MCU was stably knocked down. Similarly, MCU inhibition decreased MICU2, MICU1, and PD‑L1 expression in cisplatin‑resistant ESCC cells. Moreover, MCU knockdown substantially decreased tumor growth, EMT, and angiogenesis in ESCC and cisplatin‑resistant ESCC xenograft mice. Collectively, targeting MCU may inhibit cancer progression and alleviate cisplatin resistance in ESCC.

Syntheses, characterizations, and Hirshfeld analysis of Ag(I) and Cu(II) complexes: A novel potent Ag(I)‐based oxadiazole anticancer agent

The Ag(I) and Cu(II) complexes of the ligand, 2,2′‐(1,2,4‐oxadiazole‐3,5‐diyl) dianiline, (L; 4) were synthesized and characterized using different spectroscopic techniques. Their anticancer activities against three types of cancer cell lines were explored. The [AgL (NO3)]n complex (5) has 1D polymeric structure whereas the [CuL (NO3)2] (6) and [CuLCl2] (7) are monomeric complexes. The Ag(I) in 5 is tetra‐coordinated and has AgN2O2 coordination sphere where both L and NO3¯ are bridging the Ag(I) sites along the polymer array. In 6 and 7, the coordination environments are CuN3O3 and CuN3Cl2, respectively. In both cases, the oxadiazole ligand is a tridentate chelate via two N‐atoms from both amino groups and one N‐atom from the oxadiazole moiety. Hirshfeld analysis revealed the importance of O … H (23.5%), H … H (24.8%), and C … C (6.6%) non‐covalent interactions in the molecular packing of 5. In 6, the O … H (40.7%), N … H (4.9%), O … O (5.9%), N … O (3.2%), and C … N (2.2%) contacts are the most important. Regarding safety on normal human fibroblasts Wi‐38, MTT assay for all metal complexes especially the Ag(I) complex 5 exhibited higher safety profiles than the free oxadiazole ligand as well as the standard chemotherapeutic drug 5‐fluroruracil (5‐FU). The cytotoxic activities of complexes 5–7 surpassed 5‐FU against A549, Caco‐2, and MDA‐MB231 cell lines. 5 has the best anticancer activity (IC50 = 0.074, 0.085, and 0.533 μM, respectively) and exhibiting pronounced selectivity index up to 44.3. Quantitative PCR analysis of BAX and BCL‐2 revealed their apoptotic induction mechanism and showed that the metal complexes can repress the main oncogene BCL‐2 and enhance the expression of proapoptotic gene BAX. Again, 5 is the most potent with 14.28 folds BCL‐2 downregulation and 4.86 folds BAX upregulation.

3D dynamic cultures of HGSOC organoids to model innovative and standard therapies.

High-grade serous ovarian cancer (HGSOC) needs new technologies for improving cancer diagnosis and therapy. It is a fatal disease with few options for the patients. In this context, dynamic culture systems coupling with patient-derived cancer 3D microstructures could offer a new opportunity for exploring novel therapeutic approaches. In this study, we optimized a passive microfluidic platform with 3D cancer organoids, which allows a standardized approach among different patients, a minimum requirement of samples, multiple interrogations of biological events, and a rapid response. The passive flow was optimized to improve the growth of cancer organoids, avoiding the disruption of the extracellular matrix (ECM). Under optimized conditions of the OrganoFlow (tilting angle of 15° and an interval of rocking every 8min), the cancer organoids grow faster than when they are in static conditions and the number of dead cells is reduced over time. To calculate the IC 50 values of standard chemotherapeutic drugs (carboplatin, paclitaxel, and doxorubicin) and targeted drugs (ATRA), different approaches were utilized. Resazurin staining, ATP-based assay, and DAPI/PI colocalization assays were compared, and the IC 50 values were calculated. The results showed that in the passive flow, the IC 50 values are lower than in static conditions. FITC-labeled paclitaxel shows a better penetration of ECM under passive flow than in static conditions, and cancer organoids start to die after 48h instead of 96h, respectively. Cancer organoids are the last frontiers for ex vivo testing of drugs that replicate the response of patients in the clinic. For this study, organoids derived from ascites or tissues of patients with Ovarian Cancer have been used. In conclusion, it was possible to develop a protocol for organoid cultures in a passive microfluidic platform with a higher growth rate, faster drug response, and better penetration of drugs into ECM, maintaining the samples' vitals and collecting the data on the same plate for up to 16 drugs.

In silico examination of peptides containing selenium and ebselen Backbone To Assess Their Tumoricidal Potential

Introduction: Cancer has been one of the highest causes of morbidity and mortality in the world for decades. Owing to improved therapeutics along with detection, breast cancer mortality has been slowly reducing. The incidence of breast cancer, on the other hand, has increased gradually. More than 100 types of cancer have been identified with a wide range of treatment protocols comprising of chemotherapy, radiation therapy, hormone therapy, etc. In an attempt to curb the serious deleterious effects caused by the chemotherapeutic drugs, numerous peptide molecules are currently popular as alternatives to the standard chemotherapeutic drugs. Methods: In this study, we have carried out in silico investigations to ascertain the anti-proliferative potential of novel peptides based on selenium and ebselen, i.e. Eb-Trp-Asp, 13, Eb-Trp-Glu, 14, and Eb-Trp-Lys, 15. Analysis of protein-ligand interactions, resulting in protein-ligand complex formation, has been carried out using the AutoDockVina in PyRx aided molecular docking technique, which may be an essential indication of druggability of the test peptides. Results: The molecular docking results revealed that the screened ligands had extraordinarily strong binding interactions and affinity for the target. Conclusion: Findings suggested that novel peptide molecule Eb-Trp-Glu, 14 may be a potent anticancer agent.