Anticancer Research Articles

An Overview of the Biological Functions and Mechanisms of Action of Medicinal Plants and Seaweeds in the Shrimp Culture.

Diseases are major constraints to developing large-scale aquaculture practices in many countries. For decades, synthetic chemotherapeutic agents have been widely applied both as prophylactics and therapeutics to inhibit and control aquatic disease outbreaks. However, their use has become more restricted due to the negative impacts they have on the environment, the host and humans, as well as their limitations in preventing the emergence of antimicrobial-resistant bacteria. Therefore, there is a growing interest in the use of medicinal plants and seaweeds as potential alternatives to antibiotics and other synthetic chemotherapeutics. Medicinal plants and seaweeds can enhance the immune systems of animals, thereby providing protection against numerous diseases while minimizing the adverse effects associated with synthetic chemotherapeutics. Furthermore, the advantages of medicinal plants and seaweeds, such as their effectiveness, easy availability and ability to be applied on a large scale, make them appealing for use in the aquaculture industry. The main goal of this study was to review the existing knowledge of the effects of medicinal plants and seaweeds, as well as their extracts, on shrimp growth, immune response and disease resistance against bacterial and viral agents. Moreover, this paper discusses the application of seaweeds in shrimp culture. We also conducted a literature review to identify gaps in the research and provide recommendations for further advancement in this field of study. Further studies should focus on evaluating other physiological aspects, such as feed and mineral utilization, enzyme activities and histological examination.

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

Preclinical Assessment of the PI3Kα Selective Inhibitor Inavolisib and Prediction of Its Pharmacokinetics and Efficacious Dose in Human.

1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumors, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit.2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein.3. We characterized inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans.4. Inavolisib had a moderate permeability (1.9•10-6 cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model.5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.

A small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth.

The B-cell lymphoma 6 (BCL6) transcription factor plays a key role in establishment of germinal center (GC) formation. Diffuse large B cell lymphoma (DLBCL) originates from the GC reaction due to dysregulation of BCL6. Disrupting BCL6 and its corepressors interaction has become the foundation for rationally designing lymphoma therapies. However, BCL6 inhibitors with good activities in vitro and in vivo are rare and there are no clinically approved BCL6 inhibitors. Here, we discovered and developed a novel range of [1,2,4] triazolo[1,5-a] pyrimidine derivatives targeting BCL6/SMRT interaction. The analogue WK692 directly bound BCL6BTB, disrupted BCL6BTB/SMRT interaction and activated the expression of BCL6 downstream genes inside cells, inhibited DLBCL growth and induced apoptosis in vitro, inhibited GC formation, decreased proportion of follicular helper T (Tfh) cells and impaired immunoglobulin affinity maturation. Further studies showed that WK692 inhibited the DLBCL growth without toxic effects in vivo and synergizes with the EZH2 and PRMT5 inhibitors. Our results demonstrated that WK692 as a BCL6 inhibitor may be developed as a novel potential anticancer agent against DLBCL.

Endogenous Magnetic Lipid Droplet-Mediated Cascade-Targeted Sonodynamic Therapy as an Approach to Reversing Breast Cancer Multidrug Resistance.

Multidrug resistance (MDR) has emerged as a major barrier to effective breast cancer treatment, contributing to high rates of chemotherapy failure and disease recurrence. There is thus a pressing need to overcome MDR and to facilitate the efficient and precise treatment of breast cancer in a targeted manner. In this study, endogenous functional lipid droplets (IR780@LDs-Fe3O4/OA) were developed and used to effectively overcome the limited diffusion distance of reactive oxygen species owing to their amenability to cascade-targeted delivery, thereby facilitating precise and effective sonodynamic therapy (SDT) for MDR breast cancer. Initially, IR780@LDs-Fe3O4/OA was efficiently enriched within tumor sites in a static magnetic field, achieving the visualization of tumor treatment. Subsequently, the cascade-targeted SDT combined with the Fenton effect induced lysosome membrane permeabilization and relieved lysosomal sequestration, thus elevating drug concentration at the target site. This treatment approach also suppressed ATP production, thereby inhibiting P-glycoprotein-mediated chemotherapeutic drug efflux. This cascade-targeted SDT strategy significantly increased the sensitivity of MDR cells to doxorubicin, increasing the IC50 value of doxorubicin by approximately 10-fold. Moreover, the cascade-targeted SDT also altered the gene expression profiles of MDR cells and suppressed the expression of MDR-related genes. In light of these promising results, the combination of cascade-targeted SDT and conventional chemotherapy holds great clinical promise as an effective treatment modality with excellent biocompatibility that can improve MDR breast cancer patient outcomes.

Research progress on GSDME-mediated cell pyroptosis resulting in GSDME type hearing loss

Pyroptosis is a novel mode for programmed cell death discovered and confirmed in recent years. The Gasdermins (GSDMs) family is a key effector molecule mediating pyroptosis. As an important cause of extensive inflammatory damage and side effects of conventional chemotherapy drugs, anomalous pyroptosis has also been associated with hearing loss, tumor, and disorders of the immune system. The GSDME protein, encoded by the GSDME (DFNA5) gene, belongs to the GSDMs family and is a key factor mediating pyroptosis. Gain-of-function variants of the GSDME gene can lead to GSDME-related hearing loss, which shows an autosomal dominant inheritance. This article has reviewed the role of GSDME-mediated pyroptosis in the pathogenesis of GSDME-related hearing loss, with an aim to provide insights into the treatment of GSDME-related hearing loss.

Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is the most abundant enzyme, with approximately 1–2 million molecules per cell, acting primarily as a DNA damage sensor. It has become a promising biological target for anticancer drug studies. Enhanced PARP expression is present in several types of tumors, such as melanomas, lung cancers, and breast tumors, correlating with low survival outcomes and resistance to treatment. PARP inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy as anticancer agents both as single drugs and as sensitizers for chemo- and radiotherapy. This review explores the properties, characteristics, and challenges of PARP inhibitors, discussing their development from first-generation to third-generation compounds, more sustainable synthesis methods for discovery of new anti-cancer agents, their mechanisms of therapeutic action, and their potential for targeting additional biological targets beyond the catalytic active site of PARP proteins. Perspectives on green chemistry methods in the synthesis of new anticancer agents are also discussed.

Molecular and microbiological methods for the identification of nonreplicating Mycobacterium tuberculosis.

Chronic tuberculosis (TB) disease, which requires months-long chemotherapy with multiple antibiotics, is defined by diverse pathological manifestations and bacterial phenotypes. Targeting drug-tolerant bacteria in the host is critical to achieving a faster and durable cure for TB. In order to facilitate this field of research, we need to consider the physiology of persistent MTB during infection, which is often associated with the nonreplicating (NR) state. However, the traditional approach to quantifying bacterial burden through colony enumeration alone only informs on the abundance of live bacilli at the time of sampling, and provides an incomplete picture of the replicative state of the pathogen and the extent to which bacterial replication is balanced by ongoing cell death. Modern approaches to profiling bacterial replication status provide a better understanding of inter- and intra-population dynamics under different culture conditions and in distinct host microenvironments. While some methods use molecular markers of DNA replication and cell division, other approaches take advantage of advances in the field of microfluidics and live-cell microscopy. Considerable effort has been made over the past few decades to develop preclinical in vivo models of TB infection and some are recognized for more closely recapitulating clinical disease pathology than others. Unique lesion compartments presenting different environmental conditions produce significant heterogeneity between Mycobacterium tuberculosis populations within the host. While cellular lesion compartments appear to be more permissive of ongoing bacterial replication, caseous foci are associated with the maintenance of M. tuberculosis in a state of static equilibrium. The accurate identification of nonreplicators and where they hide within the host have significant implications for the way novel chemotherapeutic agents and regimens are designed for persistent infections.

Determination of the Optimum Architecture of Additively Manufactured Magnetic Bioactive Glass Scaffolds for Bone Tissue Engineering and Drug-Delivery Applications.

For better bone regeneration, precise control over the architecture of the scaffolds is necessary. Because the shape of the pore may affect the bone regeneration, therefore, additive manufacturing has been used in this study to fabricate magnetic bioactive glass (MBG) scaffolds with three different architectures, namely, grid, gyroid, and Schwarz D surface with 15 × 15 × 15 mm3 dimensions and 70% porosity. These scaffolds have been fabricated using an in-house-developed material-extrusion-based additive manufacturing system. The composition of bioactive glass was selected as 45% SiO2, 20% Na2O, 23% CaO, 6% P2O5, 2.5% B2O3, 1% ZnO, 2% MgO, and 0.5% CaF2 (wt %), and additionally 0.4 wt % of iron carbide nanoparticles were incorporated. Afterward, MBG powder was mixed with a 25% (w/v) Pluronic F-127 solution to prepare a slurry for fabricating scaffolds at 23% relative humidity. The morphological characterization using microcomputed tomography revealed the appropriate pore size distribution and interconnectivity of the scaffolds. The compressive strengths of the fabricated grid, gyroid, and Schwarz D scaffolds were found to be 14.01 ± 1.01, 10.78 ± 1.5, and 12.57 ± 1.2 MPa, respectively. The in vitro study was done by immersing the MBG scaffolds in simulated body fluid for 1, 3, 7, and 14 days. Darcy's law, which describes the flow through porous media, was used to evaluate the permeability of the scaffolds. Furthermore, an anticancer drug (Mitomycin C) was loaded onto these scaffolds, wherein these scaffolds depicted good release behavior. Overall, gyroid-structured scaffolds were found to be the most suitable among the three scaffolds considered in this study for bone tissue engineering and drug-delivery applications.

Natural Products-Based Anticancer Agents: Synthesis and Anticancer Activities of Funtumine Amide/sulfonamide Derivatives.

Funtumine is a pregnene-type steroidal alkaloid exhibiting moderate anticancer activity. To discovernovel natural product-based anticancer drugs, a series of novel funtumine amide/sulfonamide derivatives were papered and identified using spectroscopic techniques. Additionally, the structures of compounds 2j, 3a, and 4kwere further confirmed through X-ray diffraction analysis. Biological activity experiments conducted against three cancer cell lines revealed that several of the synthesized compounds demonstrated inhibition activities comparable to or exceeding those of the commercial anticancer agent, 5-Fluorouracil. Especially compound 4idemonstrated a notably strong growth inhibitory effect on HePG2 (IC50= 14.89 μM) and HCT116 (IC50= 15.67 μM) cell lines, while exhibiting minimal cytotoxicity towards human normal BEAS-2B cells. Preliminary structure-activity relationships (SARs) analysis indicated that the conversion of the carbonyl group at the C-20 position of funtumine to a hydroxyl group could yield more potent compounds.

Photodynamic Therapy against Colorectal Cancer Using Porphin-Loaded Arene Ruthenium Cages

Colorectal cancer (CRC) is the third most common cancer in the world, with an ongoing rising incidence. Despite secure advancements in CRC treatments, challenges such as side effects and therapy resistance remain to be addressed. Photodynamic therapy (PDT) emerges as a promising modality, clinically used in treating different diseases, including cancer. Among the main challenges with current photosensitizers (PS), hydrophobicity and low selective uptake by the tumor remain prominent. Thus, developing an optimal design for PS to improve their solubility and enhance their selective accumulation in cancer cells is crucial for enhancing the efficacy of PDT. Targeted photoactivation triggers the production of reactive oxygen species (ROS), which promote oxidative stress within cancer cells and ultimately lead to their death. Ruthenium (Ru)-based compounds, known for their selective toxicity towards cancer cells, hold potential as anticancer agents. In this study, we investigated the effect of two distinct arene-Ru assemblies, which lodge porphin PS in their inner cavity, and tested them as PDT agents on the HCT116 and HT-29 human CRC cell lines. The cellular internalization of the porphin-loaded assemblies was confirmed by fluorescence microscopy. Additionally, significant photocytotoxicity was observed in both cell lines after photoactivation of the porphin in the cage systems, inducing apoptosis through caspase activation and cell cycle progression disruptions. These findings suggest that arene-Ru assemblies lodging porphin PS are potent candidates for PDT of CRC.

Anticancer potential of isoalantolactone in testicular cancer: an analysis of cytotoxicity, apoptosis, and signaling pathways.

Testicular cancer, a highly prevalent malignancy among young adults, has witnessed an alarming rise in recent decades. This study delves into the therapeutic potential of isoalantolactone (IATL), a natural product extracted from Inula helenium and Inula racemosa, against testicular cancer. Employing MTT assays and flow cytometry, we observed a dose-dependent reduction in cell viability and induction of cell cycle arrest at sub-G1 phase with increasing IATL concentrations. Furthermore, Annexin V/PI dual staining revealed IATL-induced apoptosis. Human Apoptosis Array analysis demonstrated IATL's influence on HIF-1α and TNF R1 expression, implicating its role in cancer cell growth and death regulation. Next-generation sequencing (NGS) and pathway analysis highlighted the involvement of ferroptosis and HIF-1 signaling in IATL-mediated effects. Western blotting validated the downregulation of key proteins associated with apoptosis inhibition and activation, confirming IATL's potential as an anticancer agent. Moreover, IATL induced ferroptosis by modulating expression levels of GPX4, xCT, NRF2, and HO-1. Our findings shed light on IATL's multifaceted anticancer mechanisms, emphasizing its potential as a therapeutic candidate for testicular cancer.

Withaferin A: A potential anticancer candidate drug and its challenges for the clinical trial

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Leukemic occult infiltrative optic neuropathy presenting as optic neuritis: a case report

Isolated ocular relapses of leukemia are rare and typically present as infiltrative lesions of the optic nerve. This report presents a case of an isolated ocular relapse of leukemia in a female patient, characterized by occult infiltrative optic neuropathy. Despite the absence of leukemic cell infiltration on MRI, a 33-year-old female patient presented with optic neuritis, which resolved after intrathecal administration of chemotherapeutic agents. However, due to her non-compliance with the treatment regimen, leukemia progressed to infiltrative optic neuropathy. She refused radiation therapy, and while intrathecal injections provided temporary stabilization, they were insufficient for sustained disease control. This case uniquely documents the extended progression of an isolated ocular relapse of leukemia, evolving from an occult infiltrative lesion initially presenting as optic neuritis to a more pronounced infiltrative lesion. It suggests that leukemic optic nerve infiltration can occur in patients with leukemia even in the absence of MRI-detectable abnormalities. Radiation therapy emerges as a critical modality in the management of infiltrative lesions of the optic nerve.

Comprehensive model for simultaneous monitoring of primary tumor to metastatic cancer utilizing Prkdc and Il2rg double knockout mice

Liver cancer is the second leading cause of cancer-related deaths worldwide, motivating major scientific efforts to understand and treat this cancer type. Over 30% of patients with liver cancer progress to metastasis, which reduces the survival rate. Extensive studies on primary tumors have been conducted to improve the prognosis. However, there is a lack of appropriate and accessible models for studying the progression and metastasis of liver cancer. Moreover, conventional metastasis models do not reproduce metastasis as it occurs in patients. To address this lack of an appropriate model for the monitoring of cancer progression and evaluation of anticancer drugs, we established a spontaneous metastatic xenograft model using NSG mice subcutaneously transplanted with SK-Hep-1 cells. Compared to the conventional experimental metastasis model (intravenous transplantation), in which only lung metastasis was observed, the established spontaneous metastatic xenograft model was superior, as it showed both a primary tumor and metastatic patterns similar to those observed in human patients. Additionally, this model was successfully used to assess the antimetastatic efficacy of sorafenib. In conclusion, our results demonstrate that the established spontaneous metastatic xenograft model better reflects liver cancer metastasis and can be utilized to assess the efficacy of anticancer drugs for liver cancer.

Crystallization and crystallographic studies of human serine protease inhibitor (serpin) B9.

Serine protease inhibitor B9 (serpin B9, also known as protease inhibitor 9 or PI9) plays a critical role in regulating the immune response by specifically inhibiting granzyme B, a serine protease found in cytotoxic T lymphocytes and natural killer cells. Despite its potential as an anticancer drug target, the structural details of serpin B9 have remained elusive until now. In this study, a cleaved form of recombinant human serpin B9 was successfully prepared and crystallized. The crystals belonged to space group P212121, with unit-cell parameters a = 68.51, b = 82.32, c = 101.17 Å, and an X-ray diffraction data set was collected at 1.9 Å resolution. The structure shows that serpin B9 adopts a relaxed conformation, with its cleaved reactive-centre loop inserted into the central β-sheet. Unlike other serpins, serpin B9 shows significant structural deviations around helix D, with a larger surface cavity, which could serve as a promising target for small-molecule inhibitors.

Preparation of Disulfide/Trisulfide Core-Cross-Linked Polycarbonate Nanocarriers for Intracellular Reduction-Triggered Drug Release.

Polymeric nanocarriers have attracted significant attention in the field of anticancer drug delivery due to their unique advantages. However, designing nanocarriers that can maintain stability in the bloodstream while achieving specific drug release within tumor cells remains a major challenge. To address this issue, constructing reversible cross-linked polymeric nanocarriers that are sensitive to the intracellular reducible glutathione (GSH) characteristic of the tumor microenvironment is a promising strategy. Based on this, we designed and synthesized two novel six-membered bicyclic carbonate monomers containing disulfide (DSBC) and trisulfide (TSBC) bonds. Through a one-step ring-opening polymerization, a series of reduction-sensitive polycarbonate copolymers (i.e., PEG-PDSBC and PEG-PTSBC) were prepared, and doxorubicin (DOX)-loaded nanoparticles were fabricated using a nanoprecipitation method. The in vitro drug release behaviors of these nanoparticles were systematically investigated. The results showed that these polymers, due to the cross-linked structure formed by the ring-opening polymerization of their bicyclic monomers, could self-assemble into stable nanoparticles. Under different concentrations of glutathione, DOX-loaded PEG-PTSBC nanoparticles demonstrated faster drug release, indicating more optimized intracellular drug release properties. Further cytotoxicity experiments revealed that both types of blank nanoparticles exhibited good biocompatibility with the 4T1 and NIH-3T3 cells. Fluorescence microscopy and flow cytometry results further indicated that DOX-loaded PEG-PTSBC nanoparticles released more drugs in 4T1 cells, significantly inhibiting tumor cell growth compared with DOX-loaded PEG-PDSBC nanoparticles, with no noticeable difference in NIH-3T3 normal cells. In conclusion, this study suggests that trisulfide cross-linked polycarbonate-based nanocarriers hold promise as an anticancer drug delivery system that combines stability in the bloodstream with specific intracellular drug release, offering new insights for the development of novel, efficient, and safe anticancer nanomedicines.

A DFT study on antimonene as a drug delivery vehicle for carmustine, lomustine and nitrosourea anticancer drugs

A DFT study on antimonene as a drug delivery vehicle for carmustine, lomustine and nitrosourea anticancer drugs

Camptothecin and its derivatives: Advancements, mechanisms and clinical potential in cancer therapy.

Camptothecin (CPT), an alkaloid isolated from the Camptotheca tree, has demonstrated significant anticancer properties in a range of malignancies. However, its therapeutic efficacy is limited by its hydrophobicity, poor bioavailability, and systemic toxicity. Derivatives, analogues, and nanoformulations of CPT have been synthesized to overcome these limitations. The aim of this review is to comprehensively analyze existing studies to evaluate the therapeutic efficacy, mechanistic aspects, and clinical potential of CPT and its modified forms, including derivatives, analogues, and nanoformulations, in cancer treatment. A comprehensive literature review was performed using PubMed/Medline, Scopus, and Web of Science databases; articles were selected based on specific inclusion criteria, and data were extracted on the pharmacological profile, clinical studies, and therapeutic efficacy of CPT and its different forms. Current evidence suggests that derivatives and analogues of CPT have improved water solubility, bioavailability, and reduced systemic toxicity compared to CPT. Nanoformulations further enhance targeted delivery and reduce off-target effects. Clinical trials indicate promising outcomes with enhanced survival rates and lower side effects. CPT and its modified forms hold significant promise as potent anticancer agents. Ongoing research and clinical trials are essential for establishing their long-term efficacy and safety; the evidence overwhelmingly supports further development and clinical testing of these compounds.

From defense to offense: antimicrobial peptides as promising therapeutics for cancer

Antimicrobial peptides (AMPs), naturally occurring components of innate immunity, are emerging as a promising new class of anticancer agents. This review explores the potential of AMPs as a novel class of anticancer agents. AMPs, naturally occurring peptides with broad-spectrum antimicrobial activity, exhibit several characteristics that make them attractive candidates for cancer therapy, including selectivity for cancer cells, broad-spectrum activity, and immunomodulatory effects. Analysis of a dataset of AMPs with anticancer activity reveals that their effectiveness is influenced by various structural properties, including net charge, length, Boman index, and hydrophobicity. These properties contribute to their ability to target and disrupt cancer cell membranes, interfere with intracellular processes, and modulate the immune response. The review highlights the promising potential of AMPs as a new frontier in cancer treatment, offering hope for more effective and less toxic therapies. AMPs demonstrate promising potential in cancer therapy through multiple mechanisms, including direct cytotoxicity, immune response modulation, and targeting of the tumor microenvironment, as evidenced by extensive preclinical studies in animal models showing tumor regression, metastasis inhibition, and improved survival rates. AMPs show significant potential as cancer therapeutics through their direct cytotoxicity, immune response modulation, and tumor microenvironment targeting, with promising results from preclinical studies and early-phase clinical trials. Future research should focus on optimizing AMP properties, developing novel delivery strategies, and exploring synergistic combination therapies to fully realize their potential as effective cancer treatments, while addressing challenges related to stability, delivery, and potential toxicity.