Antitumor Research Articles

Tumor specific in situ synthesis of therapeutic agent for precision cancer therapy

BackgroundTraditional chemotherapeutic agents suffer from a lack of selectivity, poor targeting ability, and drug resistance. Developing tumor-specific therapies is crucial for precisely eliminating tumors while circumventing toxicity to normal tissues. Disulfiram (DSF), an FDA-approved drug for treating alcohol dependence, exhibits antitumor effect by forming complexes with copper ions (Cu(DDC)2). Here, we developed a Cu-doped polydopamine-based nanosystem (DSF@CuPDA-PEGM) to achieve in situ generation of toxic Cu(DDC)2.ResultsIn cancer cells with elevated H2O2 contents, CuPDA responsively degrades to release Cu ions and DSF, allowing on-site synthesis of Cu(DDC)2 with potent antitumor activity. DSF@CuPDA-PEGM exhibits excellent therapeutic efficacy against both drug-sensitive and drug-resistant cancer cells while minimizing toxicity to noncancerous cells. Moreover, DSF@CuPDA-PEGM promotes the immune response by inducing cancer cell immunogenic death, thereby augmenting anti-PD-1-based immune checkpoint blockade therapy.ConclusionA tumor-specifically degradable Cu-doped polydopamine-based nanosystem is developed to achieve in situ synthesis of antitumor compounds, providing a promising approach to precisely eliminate tumors and heighten chemo-immunotherapy.Graphical

Copper nanoparticles biosynthesis by Priestia megaterium and its application as antibacterial and antitumor agents

The growth of material science and technology places high importance on creating better processes for synthesizing copper nanoparticles. Thus, an easy, ecological, and benign process for producing copper nanoparticles (CuNPs) has been developed using Priestia sp. bacteria utilizing a variety of low-cost agro-industrial wastes and byproducts. The biosynthesis of CuNPs was conducted using glucose medium and copper ions salt solution, then it was replaced by utilizing low-cost agro-industrial wastes. UV–visible spectroscopy, dynamic light scattering (DLS), X-ray diffraction (XRD), High-resolution transmission electron microscope (HR-TEM), Attenuated Total Reflectance and Fourier transform infrared (ATR-FTIR), and zeta potential were used to characterize the biosynthesized CuNPs. The cytotoxicity of CuNPs using Vero -CCL-81 cell lines, and antibacterial and antitumor properties using human colon epithelial colorectal adenocarcinoma Caco-2-HTB-37 cell lines were assessed. The UV–visible and DLS studies revealed CuNPs formation, with a maximum concentration of 6.19 ppm after 48 h, as indicated by a 0.58 Surface plasmon resonance (SPR) within 450 nm and 57.73 nm particle size. The 16S rRNA gene analysis revealed that Priestia sp. isolate is closely related to Priestia megaterium and has been deposited in the NCBI GenBank with accession number AMD 2024. The biosynthesis with various agro-industrial wastes indicated blackstrap sugar cane molasses being the most effective for reducing CuNPs size to 3.12 nm owing to various reducing and stabilizing active compounds. The CuNPs were free of contaminants, with a sphere-shaped structure and a cytotoxicity assessment with an IC50 of 367.27 μg/mL. The antibacterial activity exhibited by the most susceptible bacteria were Bacillus cereus ATCC 11788 and Staphylococcus aureus ATCC 6538 with inhibition zones of 26.0 mm and 28.0 mm, respectively. The antitumor effect showed an IC50 dose of 175.36 μg/mL. Based on the findings, the current work sought to lower product costs and provide a practical solution to the environmental contamination issues brought on by the buildup of agricultural wastes. In addition, the obtained CuNPs could be applied in many fields such as pharmaceuticals, water purification, and agricultural applications as future aspects.

Advances in Anticancer Drug Discovery: Exploring the Untapped Potential of Natural Products for Targeted Therapies

Natural products have long been a significant source of structurally diverse and biologically active compounds, making them important for anticancer drug development. Taxol, a natural product isolated from the bark of the Pacific yew tree, is used to treat some cancers; Vincristine, a related compound that was eked out of the Madagascar periwinkle plant, treats leukemia and lymphoma. This review provides recent advances and future perspectives on developing natural-product-derived anticancer agents. We introduce celebrated examples of successfully developed natural-product-derived anticancer drugs, such as paclitaxel, doxorubicin, and camptothecin derivatives. We also discuss the hurdles of natural product-derived drug discovery, including limited availability, poor pharmacokinetics, and a lack of specificity to their intended targets. We will talk about some examples of these types of modification, including new developments in drug delivery systems, nanotechnology, and targeted drug delivery. These show how they could make natural product-derived anti-tumor drugs more effective and less harmful. It is emphasized that researchers from different fields, such as pharmacologists, catalyst chemists, drug delivery experts, rational drug designers, and nanotechnologists, will need to work together and research across disciplines for the project to succeed. This is so that problems and bottlenecks can be solved, and natural products can be used to make new anticancer drugs. Given the continuous and increasing global demand for novel anticancer drugs in the foreseeable future, natural products will remain a critically important source for discovering novel, safe, and effective anticancer drugs.

Modified Hemocyanins from Rapana thomasiana and Helix aspersa Exhibit Strong Antitumor Activity in the B16F10 Mouse Melanoma Model

Melanoma is one of the most common tumors worldwide, and new approaches and antitumor drugs for therapy are being investigated. Among the promising biomolecules of natural origin for antitumor research are gastropodan hemocyanins—highly immunogenic multimeric glycoproteins used as antitumor agents and components of therapeutic vaccines in human and mouse cancer models. A murine melanoma model established in C57BL/6 mice of the B16F10 cell line was used to study anticancer modified oxidized hemocyanins (Ox-Hcs) that were administered to experimental animals (100 μg/mouse) under different regimens: mild, intensive, and with sensitization. The solid tumor growth, antitumor response, cell infiltration in tumors, and survival were assessed using flow cytometry, ELISA, and cytotoxicity assays. Therapy with Ox-RtH or Ox-HaH resulted in the generation of enhanced specific immune response (increased levels of tumor-infiltrated mature NK cells (CD27+CD11b+) in sensitized groups and of macrophages in the intensively immunized animals) and tumor suppression. Beneficial effects such as delayed tumor incidence and growth as well as prolonged survival of tumor-bearing animals have been observed. High levels of melanoma-specific CTLs that mediate cytotoxic effects on tumor cells; tumor-infiltrating IgM antibodies expected to enhance antibody-dependent cellular cytotoxicity; type M1 macrophages, which stimulate the Th1 response and cytotoxic cells; and proinflammatory cytokines, were also observed after Ox-Hcs administration. The modified Hcs showed strong antitumor properties in different administration regimens in a murine model of melanoma with potential for future application in humans.

8213 A Splicing Modulator Inhibits Proliferation and Steroid Production of H295R Adrenocortical Cancer Cells

Abstract Disclosure: T. Tanaka: None. K. Ohe: None. T. Yanase: None. S. Kodama: None. Adrenocortical carcinoma (ACC) is a rare cancer, and treatment options are limited. The anti-tumor drug CX-4945 (Silmitasertib) is an inhibitor of Casein kinase 2 (CK2). It also inhibits cdc2-like kinase 2 (CLK2). CLK2 phosphorylates Serine/arginine rich splicing factors (SRSFs)/SR proteins and enhances exonic splicing enhancer (ESE) recognition during the pre-RNA splicing process. Anti-tumor agents targeting RNA splicing have been developed recently, and CLK inhibitors have shown anti-tumor effects against blood cancers. In this study, we analyzed the impact of CX-4945 on NCI-H295R cells. CX-4945 inhibited cell proliferation of H295R (IC50 = 6.4 µM, 72hr), and cortisol and aldosterone secretion in vitro. siRNA-induced CK2 inhibition did not alter H295R proliferation and steroid secretion. CX-4945 (150 mg/kg/day oral, 28 days) significantly reduced tumor weight in mice inoculated with H295R subcutaneously on the back. High-density microarray analysis showed reduced Nuclear receptor 5A1 (NR5A1) expression levels, indicating a possible splicing variant. RT-PCR, using a primer set that amplified the coding region, detected short variants of NR5A that were multiple exon-skipped and were not induced by suppression of CK2. The results of western blotting using an antibody that recognizes phospho-epitope of SRSFs/SR proteins showed that the phosphorylation of SRSF4 was reduced in H295R treated with CX-4945. These results suggest that CX-4945 inhibits CLK2 and decreases phosphorylated SRSF4 and ESE recognition, resulting in NR5A1 multiple exon-skipping. The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer. Presentation: 6/1/2024

8213 A Splicing Modulator Inhibits Proliferation And Steroid Production Of H295R Adrenocortical Cancer Cells

Abstract Disclosure: T. Tanaka: None. K. Ohe: None. T. Yanase: None. S. Kodama: None. Adrenocortical carcinoma (ACC) is a rare cancer, and treatment options are limited. The anti-tumor drug CX-4945 (Silmitasertib) is an inhibitor of Casein kinase 2 (CK2). It also inhibits cdc2-like kinase 2 (CLK2). CLK2 phosphorylates Serine/arginine rich splicing factors (SRSFs)/SR proteins and enhances exonic splicing enhancer (ESE) recognition during the pre-RNA splicing process. Anti-tumor agents targeting RNA splicing have been developed recently, and CLK inhibitors have shown anti-tumor effects against blood cancers. In this study, we analyzed the impact of CX-4945 on NCI-H295R cells. CX-4945 inhibited cell proliferation of H295R (IC50 = 6.4 µM, 72hr), and cortisol and aldosterone secretion in vitro. siRNA-induced CK2 inhibition did not alter H295R proliferation and steroid secretion. CX-4945 (150 mg/kg/day oral, 28 days) significantly reduced tumor weight in mice inoculated with H295R subcutaneously on the back. High-density microarray analysis showed reduced Nuclear receptor 5A1 (NR5A1) expression levels, indicating a possible splicing variant. RT-PCR, using a primer set that amplified the coding region, detected short variants of NR5A that were multiple exon-skipped and were not induced by suppression of CK2. The results of western blotting using an antibody that recognizes phospho-epitope of SRSFs/SR proteins showed that the phosphorylation of SRSF4 was reduced in H295R treated with CX-4945. These results suggest that CX-4945 inhibits CLK2 and decreases phosphorylated SRSF4 and ESE recognition, resulting in NR5A1 multiple exon-skipping. The prognosis of ACC patients with high NR5A1 expression levels is poor, independent of stage. CX-4945 may induce NR5A1 multiple exon-skipping, reduce full-length functional NR5A1, and suppress ACC growth and steroidogenesis, as a possible adjuvant in tackling this devastating cancer. Presentation: 6/1/2024

Ruthenium complexes with abiraterone acetate as antiproliferative agents

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η66-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents.

Carlos Asensio and the dawn of molecular microbial ecology.

At near 50years of the discovery of microcins, this article highlights the pivotal-but under-recognised-influence of Spanish biochemist Carlos Asensio (1925-1982) in contemporary microbiology, featuring the epistemological, sociological, and cultural impact of his scientific achievements. At a time when the intestinal microbiome is central to current biomedical research, it is due to emphasise his role in the establishment of new scientific fields that are now considered fundamental. Despite his premature death at the peak of his conceptual and experimental creativity, many of his ideas about microbial communication in complex communities inspired a generation of researchers and opened new topics reach to this day. Asensio was also a trailblazer in Spain, advocating for fundamental research within the socio-economic context of his time. He foresaw the shift towards what is now termed the knowledge-based bioeconomy, recognised the need for multidisciplinary research teams, and advocated integration science into societal and political agendas. These facets became evident during his research on microcins, low molecular weight bioactive compounds produced by enterobacteria. These molecules were hypothesised as mediators of microbial interactions in the human gut and were considered potential new antibiotics and even antitumoral agents. His research mobilised young talent and attracted unprecedented resources in Spain during the late 1970s-early 1980s. It underscored the medical value of microbial ecology and exemplified the benefits of collaboration between academia and industry. Asensio played a pivotal role in the emergence of molecular microbial ecology as a research discipline and its foundational and applied significance in biotechnology.

Possibilities of using secondary plant metabolites as antitumor agents

The review summarized the literature data of recent years on the antitumor effect of secondary plant metabolites, as well as their immunotropic and anti-inflammatory effects as components of the antitumor response. The biological basis for the action of secondary plant metabolites was characterized in the form of influence on potential targets: transcription factors, signaling pathways and receptors responsible for proliferation and apoptosis. The ways of increasing the bioavailability of secondary plant metabolites to enhance the effectiveness and possibility of their medicinal use were considered, the effects of berberine, curcumin and their derivatives were described. The search for scientific publications was conducted in foreign (PubMed) and domestic (eLibrary) electronic libraries. It was found that the multiplicity of molecular targets of secondary plant metabolites and the pleiotropy of their effects suggest the possibility of their use for the regulation of various processes in tumor and normal cells. There was a connection between the antitumor effect of secondary plant metabolites and their anti-inflammatory and immunomodulatory action. However, a significant limitation of their use was the fact that most studies were conducted on cell cultures, which was insufficient to judge the antitumor effect. Clinical trials were few and their results were contradictory. In addition, a certain contradiction has been noted between the idea of a more effective action when using a pure substance or a complex composition of various plant components. An important problem was the low bioavailability of most secondary plant metabolites, for which various methods have been proposed. Despite the long history of phytotherapy in oncology, the development of new derivatives of secondary plant metabolites with high water solubility remains relevant, including modified molecules of known secondary plant metabolites and the search for new ones with unexplored biological activity. Modern methods of chemical synthesis and delivery systems of derivatives of secondary plant metabolites, as well as the study of their effects in model experiments, seem to be promising scientific directions for the creation of new drugs with antitumor activity.

The use of sodium-glucose cotransporter type 2 inhibitors for the treatment of chronic heart failure in cancer patients receiving cardiotoxic chemotherapy. Preliminary results.

Background. Chronic heart failure (CHF) is one of the most serious and late manifestations of cardiotoxicity during treatment with antitumor drugs in cancer patients. As of today, only 2 groups of drugs have proven significant cardioprotective effects in this category of patients: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) and beta-blockers (BABs). Only recently has data emerged on the successful use of sodium-glucose cotransporter type 2 inhibitors (SGLT-2) in patients with CHF on anthracycline therapy.Aim. To evaluate the role of SGLT-2 inhibitors in the complex treatment of CHF in cancer patients receiving cardiotoxic chemotherapy.Methods. A prospective observational open study, including 60 patients with verified CHF who received cardiotoxic chemotherapy and dual cardioprotective therapy: ACEIs/ARBs + BABs (control group); and 56 patients who receive similar therapy with the addition of Dapagliflozin 10 mg 1 time in the morning (study group). The results were monitored after 6 months using laboratory and instrumental research methods, as well as additional control methods. Results. Troponin T, N-terminal prohormone of brain natriuretic peptide (NTproBNP) and left ventricular longitudinal strain (GLS) levels were compared in 47 patients who had completed all follow-up studies at 6 months. It was noted that the dynamics of troponin in both groups did not differ significantly (p0.753 and p0.260, respectively), and the level of NTproBNP significantly decreased in the study group by 7.8% compared to the control group (p0.006). Comparable data were obtained for GLS (a decrease in the study group by 6.5% in relative values) compared to the control group (p0.008)). 22 (46.8%) patients had CHF before the start of chemotherapy, and in 25 (53.2%) CHF arose during antitumor drug therapy. There were 17 (16%) deaths, but there were no deaths from heart failureinbothgroups.Conclusion. We believe that a decrease in the marker of heart failure and a less pronounced impairment of the longitudinal deformation of the left ventricle with the addition of SGLT-2 inhibitors to the basic therapy of CHF in cancer patients receiving cardiotoxic chemotherapy can slow down the progression of CHF.

Synthesis, pharmacological evaluation, and modeling of novel quaternary ammonium salts derived from β-carboline containing an imidazole moiety as angiogenesis inhibitors

In this study, a series of novel β-carboline condensed imidazolium derivatives (7a-7y) were designed and synthesized by incorporating imidazolium salt structures into β-carboline. The cytotoxicity of compounds 7a-7y was evaluated in various cancer cell lines, including lung cancer (A549), gastric cancer (BGC-823), mouse colon cancer (CT-26), liver cancer (Bel-7402), and breast cancer (MCF-7), using the MTT assay. Most compounds exhibited significant activity against one or more of the cancer cell lines. Notably, compounds 7 g, 7o, 7r, 7 s, 7u, 7v, 7x, and 7w showed the highest cytotoxic activity (IC50 < 2 μM) in the tested tumor cell lines. Compound 7x demonstrated cytotoxic activities of 1.3 ± 0.3 μM (for BGC-823), 2.4 ± 0.4 μM (against A549), 7.8 ± 0.9 μM (for Bel-7402), and 9.8 ± 1.4 μM (against CT-26). The chick chorioallantoic membrane assay revealed significant anti-angiogenic potential of compound 7x. Molecular imprinting studies suggested the anti-angiogenic effect of compound 7x might be attributed to inhibition of VEGFR2 kinase. Molecular docking and molecular dynamics further indicate that its activity may be primarily associated with the potential inhibition of VEGFR2. Our research outcomes have provided valuable lead compounds for the development of novel antitumor drugs and have offered beneficial insights for subsequent drug design and optimization.

Actin-related protein 2/3 complex subunit 1B promotes ovarian cancer progression by regulating the AKT/PI3K/mTOR signaling pathway.

Actin-related protein 2/3 complex subunit 1B (ARPC1B) is an essential subunit of the actin-related protein 2/3 (Arp2/3) complex. While there have been numerous research reports on Arp2/3 in relation to tumors, there needs to be more research on ARPC1B and its role in tumors, particularly at the pan-cancer level. Utilizing data from the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx) databases, we analyzed ARPC1B expression differences in normal, tumor, and adjacent tissues, investigating its correlation with prognosis and clinical stages in various cancers. We conducted gene enrichment analysis and explored ARPC1B's connection to the tumor immune microenvironment and its impact on anti-tumor drug resistance. In addition, in vivo and in vitro experiments have also been carried out to find the mechanism of ARPC1B on ovarian cancer (OV) proliferation and invasion. ARPC1B was highly expressed in 33 tumor types, suggesting its role as a tumor-promoting factor. Its expression correlated with poor prognosis and served as a clinical staging marker in over 10 tumor types. ARPC1B is implicated in various biological processes and signaling pathways, uniquely associated with tumor immunity, indicating immunosuppressive conditions in high-expression cases. High ARPC1B expression was linked to resistance to six anti-tumor drugs. Further experiments showed that ARPC1B can affect the proliferation, apoptosis, migration, and invasion of OV cells through the AKT/PI3K/mTOR pathway. ARPC1B is a biomarker for immune suppression, prognosis, clinical staging, and drug resistance, providing new insights for cancer therapeutics.

Unveiling the apoptotic potential of antioxidant-rich Bangladeshi medicinal plant extractives and computational modeling to identify antitumor compounds

Nowadays, there has been a significant surge in the exploration of anticancer compounds derived from medicinal plants due to their perceived safety and efficacy. Therefore, our objective was to investigate the antioxidant and antiproliferative properties, along with the phytoconstituents, of methanol extracts from various parts of 15 selected Bangladeshi medicinal plants. Standard spectrophotometric methods and confocal microscopy were utilized to assess the antioxidant and antiproliferative potential of these extracts. Additionally, phytochemical profiling was executed through gas chromatography-mass spectrometry (GC-MS) analysis. Among the extractives, Bombax ceiba bark exhibited the highest scavenging capacity against DPPH (IC50: 10.3 ± 0.7 μg/mL) and hydroxyl (IC50: 3.9 ± 0.1 μg/mL) free radicals. Furthermore, the total antioxidants, reducing power, and polyphenols of B. ceiba bark were higher than those of other extracts. B. ceiba bark also showed significant antiproliferative capacity against MCF-7 cells (86.67%) in the MTT assay, followed by Cocos nucifera roots (83.92%), Bixa orellana leaves (44.09%), and Leea macrophylla roots (25%). Moreover, B. ceiba bark, L. macrophylla roots, C. nucifera roots, and B. orellana leaves-treated Ehrlich ascites carcinoma (EAC) cells demonstrated growth inhibition rates of 87.27%, 80.45%, 42.9%, and 37.27%, respectively. Fluorescence microscopic analysis of EAC cells treated with these extracts revealed apoptotic features such as condensed chromatin, cell shrinkage, nucleus fragmentation, and membrane blebbing compared to untreated EAC cells. The GC-MS analysis of B. ceiba bark identified 18 compounds, including various alcohols, alkenes, and esters. Additionally, a molecular docking study revealed oxalic acid, cyclohexyl dodecyl ester as the most potent compound (-6.5) active against breast cancer. In summary, our results demonstrate that B. ceiba bark possesses robust antioxidant and antiproliferative properties, along with potent antitumor compounds, which could be utilized in the treatment of carcinoma.

Antiproliferative Activity of an Organometallic Sn(IV) Coordination Compound Based on 1-Methylbenzotriazole against Human Cancer Cell Lines

A motivating class of compounds with interest in the research field of biological active metallopharmaceuticals for cancer treatment is based on organometallic complexes of Sn(IV), exhibiting advantages such as improved cellular uptake and body excretion, lower toxicity, and fewer side effects compared to platinum-based drugs. In this study, the mononuclear organotin coordination complex [(CH3)2SnCl2(mebta)2] was synthesized and characterized using vibrational spectroscopy (IR, Raman), 1H NMR, 13C{1H} NMR, and X-ray crystallography. Its antiproliferative properties were thoroughly assessed across an aggressive triple-negative human breast cancer cell line. Notably, comparative studies with precursor materials verified that the observed biological activity is intrinsic to the complex itself. This study highlights the compound’s ability to induce cell fate by disrupting essential cellular functions, such as proliferation. By exploring the antiproliferative effects of organotin(IV) derivatives, we introduce a novel class of Sn complexes with 1-methylbenzotriazole (mebta), demonstrating significant potential as promising antitumor agents in the field of organotin compounds.

Neuroprotective mechanisms and ameliorative activities of quercetin in cisplatin-induced cerebellum neurotoxicity in rat models

Cisplatin (CP) is a highly effective antitumor agent, but its clinical use is limited due to critical adverse reactions including neurotoxicity. Quercetin (QC) is a naturally occurring phytochemical with promising bioactive effects. This study investigated the Neuroprotective mechanisms and ameliorative activities of quercetin in cisplatin-induced cerebellum neurotoxicity in rat models.The rats were randomly divided into five groups of six (n=6) rats. Group A, served as control. Group B, received a single dose of 10 mg/kg body weight (bwt) of CP (i.p.) on the first day. Group C received 30 mg/kg bwt of QC. Group D received a single dose of 10 mg/kg bwt CP on the first day followed by 30 mg/kg bwt of QC. Group E received 30 mg/kg bwt of QC per day followed by a single dose of 10 mg/kg bwt of CP on the last day. The treatment lasted for 35 days after which the novel-object recognition memory test (NORT) was used to assess non-spatial memory function. Brain neurochemical status was assessed and brain tissues were processed for histology.Quercetin increased weight loss and cognitive performance in CP-treated rats by enhancing the exploration of unfamiliar objects. Quercetin protects the brain from CP-mediated alterations in oxidative status, as well as brain metabolic enzyme indicators. It also decreased IL-6, IL-1, and TNF-α, and NF-ĸB expression, restored brain metabolic enzyme activities, increased neurotransmitters, and prevented neuromorphological alterations.In conclusion, quercetin protects rats’ brains against CP-induced cerebellum neurotoxicity via oxidative stress inhibition and down-regulation of inflammation.

Evaluation of the in vivo acute toxicity and in vitro genotoxicity and mutagenicity of synthetic β-carboline alkaloids with selective cytotoxic activity against ovarian and breast cancer cell lines

The aim of this study was to evaluate the in vitro cytotoxic, genotoxic, and mutagenic potential and to determine the in silico ADME parameters of two synthetic β-carboline alkaloids developed as prototypes of antitumor agents (NQBio-06 and NQBio-21). Additionally, acute toxicity of the compounds was evaluated in mice. The results from the MTT assay showed that NQBio-06 presented higher cytotoxicity in the ovarian cancer cell line TOV-21G (IC50 = 2.5 µM, selectivity index = 23.7). NQBio-21 presented an IC50 of 6.9 µM and a selectivity index of 14.5 against MDA-MB-231 breast cancer cells. Comet assay results showed that NQBio-06 did not induce chromosomal breaks in vitro, but NQBio-21 was genotoxic with and without metabolic activation (S9 fraction). Micronucleus assay showed that both compounds were mutagenic. In addition, metabolic activation enhanced this effect in vitro. The in silico predictions showed that the compounds met the criteria set by Lipinski's rules, had strong prediction for intestinal absorption, and were possible substrates for P-glycoprotein. The in vivo results demonstrated that both the compounds exhibited low acute toxicity. These results suggest that the mechanisms underlying the cytotoxicity of NQBio-06 and NQBio-21 are related to DNA damage induction and that the use of S9 enhanced these effects. In vivo analysis showed signs of toxicity after a single administration of the compounds in mice. These findings highlight the potential of β-carboline compounds as sources for the development of new anticancer chemotherapeutic agents.

Is there a possibility that P-glycoprotein reduces reproductive toxicity in males but breast cancer resistance protein does not?

In traditional understanding, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are regarded as efflux transporters that can decrease the concentration of their substrates in the testis, thereby reducing reproductive toxicity in males (RTM) and protecting spermatogenesis. However, there is currently no direct pharmacological evidence demonstrating that P-gp and BCRP can reduce the occurrence of drug-induced RTM. In this study, we chose small molecule targeted anti-tumor agents as model drugs and systematically retrieved and collected information on the transporters and RTM for these drugs, followed by correlation analysis. The results showed a lower incidence of RTM for P-gp substrate drugs, which aligns with previous knowledge. Surprisingly, BCRP substrate drugs exhibited higher rates of RTM in various dimensions, contradicting previous notions. This discrepancy may be attributed to the differential distribution and transport directions of P-gp and BCRP on the blood-testis barrier (BTB). For the first time, this study may provide clues that BCRP may facilitate the passage of exogenous compounds across the BTB, increasing the occurrence of RTM, rather than protecting spermatogenesis as traditionally believed. Furthermore, this study provides the first direct verification of the role of P-gp in reducing RTM and protecting spermatogenesis.

Design, Synthesis, and Biological Evaluation of Novel Apigenin Derivatives as Potential Antitumor Agents

Design, Synthesis, and Biological Evaluation of Novel Apigenin Derivatives as Potential Antitumor Agents

New Application of Ombuoside in Protecting Auditory Cells from Cisplatin-induced Ototoxicity via the Apoptosis Pathway

Hearing loss is caused by many factors including ototoxic drug-induced hair cell damage. Ombuoside, an antioxidant isolated from Gynostemma pentaphyllum, has been suggested to serve as a new neuroprotective drug. However, the role of ombuoside in protecting inner ear hair cells from ototoxic drug-induced damage has not been investigated. Here, we demonstrated the protective potential of ombuoside in mitigating drug-induced ototoxicity in vivo and in vitro. We used cisplatin, a highly ototoxic anti-tumor drug, to induce hair cell damage. Our results showed that ombuoside significantly increased the survival of cisplatin-treated HEI-OC1 cells. Further mechanism research suggested that ombuoside protects HEI-OCI cells from cisplatin-induced apoptosis by reducing the cisplatin-induced upregulation of apoptosis-promoting proteins Bax, Bak, as well as apoptosis indicator proteins cytochrome C and cleaved-caspase-3, and the downregulation of apoptosis-inhibiting proteins Bcl-2. Ombuoside also protects the cells from the excessive ROS production and mitochondrial membrane depolarization triggered by cisplatin. These results demonstrated the potential for ombuoside in protecting hair cells from cisplatin by suppressing ROS generation and the mitochondrial apoptotic cascade. Ombuoside showed promise in protecting hair cells from cisplatin-induced apoptosis by suppressing ROS generation and the mitochondrial apoptotic cascade. Furthermore, ombuoside co-treatment in mouse cochlear explants and zebrafish lateral neuromasts rescued the decreased number and deformed morphology of hair cells resulting from cisplatin exposure. These findings further validated our conclusions and indicated that ombuoside is a potential protector against hearing loss caused by ototoxicity as a clinical side effect of cisplatin.

Design, synthesis and antitumor effects of lupeol quaternary phosphonium salt derivatives

Lupeol is a natural pentacyclic triterpenoid with a wide range of biological activities. To improve the water solubility and targeting of lupeol, in the following study, we synthesized 27 lupeol derivatives in the first series by introducing lipophilic cations with lupeol as the lead compound. Through the screening of different cancer cells, we found that some of the derivatives showed better activity than cisplatin against human non-small cell lung cancer A549 cells, among which compound 6c was found to have an IC50 value of 1.83 μM and a selectivity index of 21.02 (IC50MRC-5/IC50A549) against A549 cells. To further improve the antiproliferative activity of the compounds, we replaced the ester linkage of the linker with a carbamate linkage and synthesized a second series of five lupeol derivatives which were screened for activity, among which compound 14f was found to have an IC50 value of 1.36 μM and a selectivity index of 15.60 (IC50MRC-5/IC50A549) against A549 cells. We further evaluated the bioactivity of compounds 6c and 14f and found that both compounds induced apoptosis in A549 cells, promoted an increase in intracellular reactive oxygen species and decrease in mitochondrial membrane potential, and inhibited the cell cycle in the S phase. Of the compounds, compound 14f showed stronger bioactivity than compound 6c. We then selected compound 14f for molecular-level Western blot evaluation and in vivo evaluation in the zebrafish xenograft A549 tumor cell model. Compound 14f was found to significantly downregulate Bcl-2 protein expression and upregulate Bax, Cyt C, cleaved caspase-9, and cleaved caspase-3 protein expression, and 14f was found to be able to inhibit the proliferation of A549 cells in the zebrafish xenograft model. The above results suggest that compound 14f has great potential in the development of antitumor drugs targeting mitochondria.