Anticancer Research Articles

Design, synthesis, and in vitro and in vivo biological evaluation of triazolopyrimidine hybrids as multitarget directed anticancer agents.

In response to the urgent need for new anti-proliferative agents, four novel series of triazolopyrimidine compounds (7a-e, 9a-d, 11a-f, and 13a-e) were synthesized and evaluated for in vitro anticancer efficacy against HCT116, HeLa, and MCF-7 cell lines. Compound 13c emerged as the most potent, with IC50 values of 6.10, 10.33, and 2.42 μM respectively, while 11e and 7c also showed strong activity. In multi-target suppression tests, 13c exhibited the highest inhibition against EGFR, TOP-II, HER-2, and ARO (IC50: 0.087, 31.56, 0.078, and 0.156 μM, respectively). Flow cytometry revealed 13c's ability to suppress the S-phase cell population in MCF-7 cells. In vivo studies of 13c demonstrated significant tumor growth inhibition, comparable to the positive control. Molecular docking studies supported the experimental findings, confirming the binding of the novel motifs to the target enzymes' active sites. This comprehensive evaluation highlights the potential of these triazolopyrimidine compounds, particularly 13c, as promising anticancer agents, warranting further investigation.

Tubulin acetyltransferases access and modify the microtubule luminal K40 residue through anchors in taxane-binding pockets.

Acetylation at α-tubulin K40 is the sole post-translational modification preferred to occur inside the lumen of hollow cylindrical microtubules. However, how tubulin acetyltransferases access the luminal K40 in micrometer-long microtubules remains unknown. Here, we use cryo-electron microscopy and single-molecule reconstitution assays to reveal the enzymatic mechanism for tubulin acetyltransferases to modify K40 in the lumen. One tubulin acetyltransferase spans across the luminal lattice, with the catalytic core docking onto two α-tubulins and the enzyme's C-terminal domain occupying the taxane-binding pockets of two β-tubulins. The luminal accessibility and enzyme processivity of tubulin acetyltransferases are inhibited by paclitaxel, a microtubule-stabilizing chemotherapeutic agent. Characterizations using recombinant tubulins mimicking preacetylated and postacetylated K40 show the crosstalk between microtubule acetylation states and the cofactor acetyl-CoA in enzyme turnover. Our findings provide crucial insights into the conserved multivalent interactions involving α- and β-tubulins to acetylate the confined microtubule lumen.

Efficacy and safety of Shengjiang Xiexin decoction on irinotecan-induced diarrhea in small cell lung cancer patients: a multicenter, randomized, double-blind, placebo-controlled trial

BackgroundIrinotecan is a standard chemotherapeutic agent in small cell lung cancer (SCLC), however, as a common adverse reaction, diarrhea limits the use of irinotecan. Shengjiang Xiexin decoction (SXD) has been used in various gastrointestinal diseases in China two thousand years ago. We designed this clinical trial to supply more evidences on the use of SXD as prophylaxis for irinotecan-induced diarrhea, especially for high-risk population predicted by gene testing of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1).MethodsIn this clinical trial, 120 patients with SCLC were recruited from six hospitals in China. They received two cycles of chemotherapy, meanwhile they were randomized to receive SXD or placebo for 14 days of oral administration in each cycle of chemotherapy. The primary outcome is the incidence of diarrhea. And secondary outcomes include the the degree of diarrhea and neutropenia, the number of chemotherapy cycles with diarrhea, first occurrence time and duration of diarrhea. To evaluate the effect of SXD on the intestine, a rat model with delayed-onset diarrhea induced by irinotecan was established, and the expression of inflammatory factors including IL-1β, IL-6 and TNF-α, anti-inflammatory factors including IL-10, TGF- β in jejunal tissue was detected by ELISA.Results101 patients (53 in SXD group, 48 in placebo group) completed the trial. The incidence of diarrhea in SXD group and placebo group were 26.42% (14/53) and 52.08% (25/48), respectively (P < 0.05), and the degree of diarrhea also had significant differences (P < 0.05). In UGT1A1 high-risk population, the incidence of diarrhea in two groups were 9.09% and 66.67% (P < 0.05), but there was no significant differences in UGT1A1 low-risk population. The incidence of neutropenia with degree 1–3 between two groups was 20.75% vs 20.83%, 13.21% vs 18.57%, 9.43% vs 20.83% (P < 0.05). No severe adverse events were reported in any group. And animal studies had shown SXD reduced content of IL-1β, IL-6, TNF-α, increased content of IL-10, TGF-β in jejunum tissue.ConclusionsSXD had a prophylactic effect in the diarrhea induced by irinotecan, especially for UGT1A1 high-risk population, and this effect from SXD appeared to be maintained the completion of chemotherapy schedule. The mechanism of action of SXD was related to the regulation of inflammatory factors.Trial registration Chinese Clinical Trial Register: ChiCTR1800018490. Registered on 20 September 2018. https://www.chictr.org.cn/showproj.html?proj=25250. The preliminary protocol of this clinical study has been published in the journal “Trials” in the form of protocol before this paper (Deng et al. in Trials 21:370, 2020).

Targeting mitochondrial dynamics: an in-silico approach for repurposing antifungal drugs in OSCC treatment

Drug repurposing for cancer treatment is a valuable strategy to identify existing drugs with known safety profiles that could combat the neoplasm, by reducing costs. Oral squamous cell carcinoma, an ulcer-proliferative lesion on the mucosal epithelium, is the most common oral malignancy. About 10% of cancer patients within the Indian subcontinent suffer from OSCC, primarily due to chewing of betel plant derivatives. Concomitant administration of the chemotherapeutic agent (Cisplatin/Paclitaxel) is the treatment of choice. Analysis of the oral mycobiome of OSCC patients has projected the role of Candida albicans in potentiating OSCC. Hence, repurposing antifungal drugs emerges as a promising approach, as these drugs could target both the cancer cells and the infection. Cancer cells often have heightened energy requirements, and targeting mitochondrial proteins to disrupt mitochondrial division and induce dysfunction contributing to cell death, offers a method for treating OSCC. We identified 18 mitochondrial targets playing a crucial role in the maintenance of mitochondrial homeostasis. They were docked against 125 antifungal ligand molecules sourced from PUBCHEM. Ligand profiling was performed using Lipinski’s rule of 5, SwissADME and ProTox. Also, molecular dynamics and MM-PBSA were performed to validate our results. Among all protein ligand interactions, we observed that targeting DRP1 with itraconazole yielded superior binding and stability. Overall, lower toxicity and thumping ADME properties solidified the choice of ligand. We hope this experimental approach will enable us to provide a basis for selecting a lead molecule for a possible novel nano-formulation and validate our finding through in-vitro cell line-based testing.

Intestinal human carboxylesterase 2 (CES2) expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice.

Carboxylesterase 2 (CES2) is expressed mainly in liver and intestine, but most abundantly in intestine. It hydrolyzes carboxylester, thioester, and amide bonds in many exogenous and endogenous compounds, including lipids. CES2 therefore not only plays an important role in the metabolism of many (pro-)drugs, toxins and pesticides, directly influencing pharmacology and toxicology in humans, but it is also involved in energy homeostasis, affecting lipid and glucose metabolism. In this study we investigated the pharmacological and physiological functions of CES2. We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes (Ces2-/- strain) as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2-/- background. We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2-/- mice, and tissue-specifically decreased by intestinal and hepatic human CES2 (hCES2) activity. The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2-/- mice, but only marginally rescued by hCES2 expression. On the other hand, Ces2-/- mice exhibited fatty liver, adipositis, hypercholesterolemia and diminished glucose tolerance and insulin sensitivity, but without body mass changes. Paradoxically, hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size, adipose tissue mass and overall body weight, suggesting a "healthy" obesity phenotype. In contrast, intestinal hCES2 expression efficiently rescued all phenotypes, and even improved some parameters, including body weight, relative to the wild-type baseline values. Our results suggest that the induction of intestinal hCES2 may combat most, if not all, of the adverse effects of metabolic syndrome. These CES2 mouse models will provide powerful preclinical tools to enhance drug development, increase physiological insights, and explore potential solutions for metabolic syndrome-associated disorders.

IGF2BP3-dependent N6-methyladenosine modification of USP49 promotes carboplatin resistance in retinoblastoma by enhancing autophagy via regulating the stabilization of SIRT1.

Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin-specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m6A-dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49-mediated CBP resistance. Our findings delineate a novel molecular network involving USP49-mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.

Evaluating N-acetylcysteine as a Protective Agent Against Chemotherapy-induced Neuropathy in Breast Cancer: A Triple-blind, Randomized Clinical Trial.

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant clinical issue that affects patients' quality of life and can limit the dosing of chemotherapeutic agents. N-acetylcysteine (NAC) has been proposed as a potential chemoprotective agent against CIPN due to its antioxidant properties. This study aimed to investigate the efficacy of oral NAC in preventing and controlling taxane-induced neuropathy in patients with breast cancer. This randomized, triple-blind, placebo-controlled trial included 80 breast cancer patients undergoing taxane-based chemotherapy. Participants were divided into 2 groups: an intervention group receiving 1200mg of oral NAC in divided doses per day and a placebo group. Patients were evaluated for neuropathy grade and functional status at 1 and 12 weeks postintervention. Our analysis revealed no significant difference in the incidence and severity of neuropathy between the intervention and placebo groups at 1 (P=0.328) and 12 weeks (P=0.569) postchemotherapy. Baseline characteristics such as age, number of treatment cycles, and disease stage were similar between groups, indicating a homogeneous population. Oral NAC at a dose of 1200mg per day did not significantly reduce the incidence or severity of taxane-induced neuropathy. These findings suggest that the oral bioavailability of NAC may be insufficient to exert a protective effect and that future studies should consider alternative dosing strategies or routes of administration. The need for further research to optimize NAC's chemoprotective role in CIPN remains evident.

Corrigendum: Network-based prediction of anti-cancer drug combinations

Corrigendum: Network-based prediction of anti-cancer drug combinations

Anticancer Drug Development, Pharmaceutical Progress

Anticancer drug development is becoming complex and demanding because human cancer leads to 12% of global human mortality. Chemical and pharmacological breakthroughs play leading roles in updating drug evaluation and development for different types of tumors. Chemical and pharmacological breakthroughs manifest in different facets. A large proportion of financial and workload increases in drug discovery must be paid off. In front of complexity, difficulties, and financial increase of drug development, evaluative promotion must go miniature- wise and single-cell-wise. Multi-omics knowledge and technology are greatly expanded and understood in depth. This type of technical trend is suitable for current experimental exploration and clinical occasions. Technical and pharmacologic advances are especially emphasized to address this trend. Presently, the anticancer pharmaceutical study is multi-faceted and risk-taking. To keep up this momentum, multi-disciplinary drug evaluation, clinical selection, and combination principles should be discovered. Past and futuristic chemical and pharmacological interactions and breakthroughs are discussed. In summary, the landscape of pharmaceutical investigation should be integrated with chemical and pharmacological knowledge in every facet of drug development and clinical personalization.

Design, synthesis and antitumor activity of triphenylphosphonium-linked derivatives of quinazolinone

Cancer is the leading cause of human death. Quinazolinone heterocyclic compounds have a variety of biological activities and have been extensively studied in recent years, especially for their potential anticancer activity. The triphenylphosphonium moiety (TPP+) has become a very important lipophilic cation, especially concerning its application the development of anticancer agents. In this work, we designed and synthesised 24 new TPP+ -conjugated quinazolinone derivatives, which have alkylated TPP+ at the N-3 position and different small group substitutions at the C-6 position, and their antiproliferative activity was evaluated in three cancer cell lines (human alveolar adenocarcinoma cells (A549), human hepatoblastoma cells (HepG2) and human breast cancer cells (MCF-7)) and human normal liver cells (QSG-7701). The cytotoxicity screening results showed that some derivatives exhibited effective inhibitory effects in cancer cells. Among them, the compound 5k–o showed better antiproliferative activity than the positive control drug gefitinib on MCF-7 and A549 cells. The most active compounds being 5o, with IC50 values of 6.56, 14.52 and 7.51 µM in MCF-7 cells, HepG2 cells and A549 cells, respectively. Compound 5o may be a promising compound for cancer treatment worthy of further study.

Cisplatin-encapsulated TRAIL-engineered exosomes from human chorion-derived MSCs for targeted cervical cancer therapy

BackgroundCisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources.MethodsHuman chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo.ResultsCompared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo.ConclusionsDDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice.Graphical abstract

Methyl-β-cyclodextrin Enhances Tumor Cellular Uptake and Accumulation of α-Linolenic Acid-Paclitaxel Conjugate Nanoparticles.

Improving nanomedicine uptake by tumor cells is key to achieving intracellular drug delivery. In this study, we found that methyl-β-cyclodextrin (MβCD) can significantly promote the intracellular accumulation of nanoparticulated α-linolenic acid-paclitaxel conjugates (ALA-PTX NPs) via enhanced clathrin-mediated endocytosis and limited degradation in lysosomes. Our in vitro results indicated that MβCD not only reduced the plasma membrane cholesterol content and increased plasma membrane fluidity, leading to ALA-PTX NPs being more easily incorporated into the plasma membrane, further enhancing membrane fluidity and making the plasma membrane more susceptible to tensile deformation, forming intracellular vesicles to enhance ALA-PTX NP cellular uptake, but also destroyed lysosomes and then limited ALA-PTX NPs' degradation in lysosomes. In HepG2 tumor-bearing mice, MβCD was also able to enhance the antitumor activity of ALA-PTX NPs in vivo. Moreover, we found that MβCD specifically promoted PUFA-paclitaxel conjugate NP cellular uptake. The cellular uptake of PTX liposome which shares an endocytosis pathway with ALA-PTX NPs could be enhanced by MβCD combined with ALA or ALA-PTX NPs. Therefore, we suggested that MβCD combined with polyunsaturated fatty acid-conjugation would be an effective strategy for improving intracellular delivery of nanoparticulated chemotherapeutic drugs used for combination administration to enhance antitumor efficiency.

Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (Dox) is a commonly used chemotherapy drug effective against a range of cancers, but its clinical application is greatly limited by dose-dependent and cumulative cardiotoxicity. Mitochondrial dysfunction is recognized as a key factor in Dox-induced cardiotoxicity, leading to oxidative stress, disrupted calcium balance, and activation of apoptotic pathways. Recent research has emphasized the potential of small molecules that specifically target mitochondria to alleviate these harmful effects. This review provides a comprehensive analysis of small molecules that offer cardioprotection by preserving mitochondrial function in the context of doxorubicin-induced cardiotoxicity (DIC). The mechanisms of action include the reduction of reactive oxygen species (ROS) production, stabilization of mitochondrial membrane potential, enhancement of mitochondrial biogenesis, and modulation of key signaling pathways involved in cell survival and apoptosis. By targeting mitochondria, these small molecules present a promising therapeutic strategy to prevent or reduce the cardiotoxic effects associated with Dox treatment. This review not only discusses the mechanistic actions of these agents but also emphasizes their potential in improving cardiovascular outcomes for cancer patients. Gaining insight into these mechanisms can help in creating more effective strategies to safeguard the heart during chemotherapy, allowing for the ongoing use of Dox with a lower risk to the patient's cardiovascular health. This review highlights the critical role of mitochondria-targeted therapies as a promising approach in addressing DIC.

Research on the Therapeutic Effect of Qizhu Anti Cancer Recipe on Colorectal Cancer Based on RNA Sequencing Analysis.

Colorectal cancer is one of the common malignant tumors in clinical practice, and traditional Chinese medicine, as an important adjuvant treatment method, plays important roles in the treatment of malignant tumors. This study aims to explore the mechanism of action of the Qizhu anti-cancer recipe on colorectal cancer through transcriptome sequencing. The control group and Qizhu anti-cancer recipe group were established separately, and sequencing of the cells of the two groups was performed using the Illumina sequencing platform. Two sets of Differentially Expressed Genes (DEGs) were screened using the DESeq2 algorithm, and Principal Component Analysis (PCA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, Disease Ontology (DO), and Protein-Protein Interaction (PPI) were used to comprehensively analyze the molecular functions and signaling pathways enriched by DEGs. A total of 122 DEGs were identified through differential analysis, including 24 upregulated genes and 98 downregulated genes. GO analysis showed that DEGs were mainly enriched in functions such as alkaline phase activity, ion transport, cell differentiation, etc.; KEGG analysis showed that DEGs were mainly enriched in pathways such as Thiamine metabolism, apoptosis, signaling pathways regulating pluripotency of stem cells, cellular senescence and so on. Reactom analysis showed that DEGs were mainly enriched in response pathways such as EGR1,2,3 bind to the NAB2 promoter, EGR binds ARC gene, EGR-dependent NAB2 gene expression, etc.; DO analysis showed that differentially expressed genes were mainly enriched in diseases such as disease of cellular proliferation, disease of anatomical entity, organ system cancer, etc.; PPI analysis identified key differentially expressed genes, including DDIT3, CHAC1, TRIB3, and ASNS. Based on transcriptome sequencing and bioinformatics analysis, it was found that the Qizhu anti-cancer recipe may involve DEGs and signaling pathways in the treatment of colorectal cancer. Our study may provide potential drug targets for developing new treatment strategies for colorectal cancer.

Thiazolopyrimidinium systems with a quaternized nitrogen atom as promising anticancer agents

Thiazolopyrimidinium systems with a quaternized nitrogen atom are attracting increasing attention in the development of new anticancer drugs. Their unique chemical structure and potential biological properties make them promising candidates for the development of effective drugs. In recent years, researches have shown that these compounds have significant activity against various types of tumors due to their ability to interact with cellular targets, disrupting processes critical for the survival and proliferation of tumor cells. This review examines the current state of researches on thiazolopyrimidines, including synthesis, mechanisms of action, and evaluation of their antitumor potential, with an emphasis on the importance of the quaternized nitrogen atom in their biological activity.

Emerging Trends in Quinoxaline‐based Analogs as Protein Kinase Inhibitors: Structural Developments and SAR Insights

Cancer remains a leading cause of mortality and has been recognized as a significant global health concern. Although numerous effective anticancer agents are available; most of the current drugs lack specificity, leading to common side‐effects associated with chemotherapy. Recent research, however, offers promise for developing more targeted and safer anticancer therapies through protein kinase inhibition. Quinoxaline derivatives represent a notable class of heterocyclic compounds. The extensive spectrum of biological activities demonstrated by quinoxalines has garnered substantial research interest. Quinoxaline and its derivatives have emerged as a novel class of chemotherapeutic agents with significant activity against various tumors through protein kinase inhibition. This review aims to elucidate recent advancements in the quinoxaline derivatives targeting protein kinase along with structural developments and structure‐activity relationships associated with these compounds.

Enhancing Anti-PD-1 Immunotherapy by Targeting MDSCs via Hepatic Arterial Infusion in Breast Cancer Liver Metastases

Background: Surgery, chemotherapy, and radiation often have limited utility for advanced metastatic disease in the liver, and despite its promising activity in select cancers, PD-1 blockade therapy similarly has minimal benefit in this setting. Curaxin, CBL0137, is an experimental anti-cancer drug that disrupts the binding of DNA to histones, destabilizes chromatin, and induces Z-DNA formation which may stimulate anti-tumor immune responses. Methods: Murine cell lines of colon (CT26) and breast (4T1) cancer were interrogated for survival and CBL0137-associated DNA changes in vitro. Immunocompetent models of liver metastases followed by CBL0137 hepatic arterial infusion (HAI) were used to examine in vivo tumor cell DNA alterations, treatment responses, and the immune contexture associated with CBL0137, both alone and in combination with anti-PD-1 therapy. Results: CBL0137 induced immediate changes to favor tumor cell death in vitro and in vivo with an efficient tumor uptake via the HAI route. Toxicity to CBL0137 was minimal and anti-tumor treatment effects were more efficient with HAI compared to intravenous delivery. Immune effects were pronounced with CBL0137 HAI with concurrent depletion of a specific population of myeloid-derived suppressor cells and maintenance of effector T cell populations. Conclusions: Combination of CBL0137 HAI with PD-1 blockade improved survival in 4T1 tumors but not in CT26 tumors, and therapeutic efficacy relies on the finding of simultaneous and targeted depletion of myeloid-derived suppressor cells and skewing of T cell populations to produce synergy with PD-1 blockade therapy.

Surface Coating of ZIF-8 Nanoparticles with Polyacrylic Acid: A Facile Approach to Enhance Chemical Stability for Biomedical Applications.

Nanoparticles of zeolitic imidazole framework-8 (ZIF-8 NPs), which are the subclass of metal-organic frameworks consisting of Zn ion and 2-methylimidazole, have been identified as promising drug carriers since their large microporous structure is suited for encapsulating hydrophobic drug molecules. However, one of the limitations of ZIF-8 NPs is their low stability in physiological solutions, especially in the presence of water and phosphate anions. These molecules can interact with the coordinatively unsaturated Zn sites at the external surface to induce the degradation of ZIF-8 NPs. In this study, herein a facile approach is reported to enhance the chemical stability of ZIF-8 NPs by surface coating with polyacrylic acid (PAA). The PAA-coated ZIF-8 (PAA-ZIF-8) NPs are prepared by mixing ZIF-8 NPs and PAA in water. PAA coating inhibits the degradation of ZIF-8 NPs in water as well as phosphate-buffered saline over 6 days, which seems to be due to the coordination of carboxyl groups of PAA to the reactive Zn sites. Furthermore, the PAA-ZIF-8 NPs loaded with the anticancer drug doxorubicin (Dox) show cytotoxicity in human colon cancer cells. These results clearly show the feasibility of the PAA coating approach to improve the chemical stability of ZIF-8 NPs without impairing their drug delivery capability.

Carboplatin-loaded zeolitic imidazolate framework-8: Induction of antiproliferative activity and apoptosis in breast cancer cell.

The challenge with breast cancer is its ongoing high prevalence and difficulties in early detection and access to effective care. A solution lies in creating tailored metal-organic frameworks to encapsulate anticancer drugs, enabling precise and targeted treatment with less adverse effects and improved effectiveness. Zeolitic imidazolate framework-8 (ZIF-8) and carboplatin (CP)-loaded ZIF-8 were synthesized and characterized using various analytical techniques. High Resolution-transmission electron microscopy of ZIF-8 and CP@ZIF-8 indicates that the particles had a spherical shape and were nanosized. The drug release rate of CP is 98% under an acidic medium (pH 5.5) because of the dissolution of ZIF-8 into its coordinating ions, whereas 35% in a physiological medium (pH 7.4) with the addition of CP, the high porosity, and pore diameter of ZIF-8 decrease from 1243 to 1041m2/g. Breast cancer MCF-7 cells were shown greater IC50 in CP@ZIF-8 (15.01±3.03µg/mL) than free CP (34.98±4.25µg/mL) in an in vitro cytotoxicity assessment. The cytotoxicity of the CP@ZIF-8 against MCF-7 cells was studied using the methylthiazolyldiphenyl-tetrazolium bromide method. The morphological changes were examined using fluorescent staining (acridine orange-ethidium bromide and Hoechst 33258) methods. The comet assay assessed the DNA fragmentation (single-cell gel electrophoresis). The results from the study revealed that CP@ZIF-8 can be used in the treatment of breast cancer.

Effective Synthesis of C20-Epi-Isothiocyanato-Salinomycin and its Thiourea Derivatives as Potential Anticancer Agents.

Salinomycin, a naturally occurring polyether ionophore antibiotic isolated from Streptomyces albus, has been demonstrated potent cytotoxic activity against a variety of cancer cell lines. In particular, it exhibits selective targeting of cancer stem cells. However, systemic toxicity, drug resistance and low bioavailability of the drug significantly limit its potential applications. In this study, the C20-epi-isothiocyanate of salinomycin was designed and synthesized, and then reacted with amines as a versatile synthon to assemble a series of salinomycin thiourea derivatives, which improved the druggability of salinomycin. The antiproliferative activities of the compounds were evaluated in vitro against A549, HepG2, HeLa, 4T1, and MCF-7 cancer cell lines using the CCK-8 assay. The pharmacological results showed that some salinomycin thiourea derivatives exhibited excellent inhibitory activity against at least one of the tested tumor cells and high selectivity. Further mechanistic studies showed that compound 9 f, containing a 3,5-difluorobenzyl moiety, could directly induce apoptosis, probably by increasing caspase-9 protein expression and cell cycle arrest in G1 phase in a concentration dependent manner.