Plumbagin is an important naphthoquinone with potent anticancer properties besides multitudinous uses in healthcare. It is produced in a limited number of species and families but mostly in the roots of Plumbaginaceae family members. The biosynthetic pathway and the genes that regulate plumbagin synthesis are not completely known, but details of these are being revealed. Several species, including Plumbago, Drosera, and others, are being uprooted for the extraction of plumbagin by pharmaceutical industries, leading to the destruction of natural habitats. The pharmaceutical industry is therefore facing an acute shortage of plant material. This necessitates enhancing the accumulation of plumbagin using suspensions and hairy roots to meet market demands. Many factors, such as the aggregate size of the inoculum, stability of the culture, and the sequential effects of elicitors, immobilization, and permeabilization, have been demonstrated to act synergistically and markedly augment plumbagin accumulation. Hairy root cultures can be used for the large-scale production, growth, and plumbagin accumulation, and the exploration of their efficacy is now imperative. The secretion of compounds into the spent medium and their in situ adsorption via resin has remarkable potential, but this has not been thoroughly exploited. Improvements in the quality of biomass, selection of cell lines, and production of plumbagin in bioreactors have thus far been sporadic, and these parameters need to be further exploited. In this review, we report the advances made relating to the importance of stable cell line selection for the accumulation of compounds in long-term cultures, hairy root cultures for the accumulation of plumbagin, and its semicontinuous production via total cell recycling in different types of bioreactors. Such advances might pave the way for industrial exploitation. The steps in the biosynthetic pathway that are currently understood might also aid us in isolating the relevant genes in order to examine the effects of their overexpression or heterologous downregulation or to edit the genome using CRISPR-Cas9 technology in order to enhance the accumulation of plumbagin. Its potential as an anticancer molecule and its mode of action have been amply demonstrated, but plumbagin has not been exploited in clinics due to its insolubility in water and its highly lipophilic nature. Plumbagin-loaded nanoemulsions, plumbagin-silver, or albumin nanoparticle formulations can overcome these problems relating to its solubility and are currently being tried to improve its bioavailability and antiproliferative activities, as discussed in the current paper.

Several new coumarin-isoxazole-pyridine hybrids were synthesized through a 1,3-dipolar cycloaddition reaction of nitrile oxides, prepared in situ from pyridine aldehyde oximes, with propargyloxy- or propargylaminocoumarins in moderate-to-good yields. Synthetic modifications were applied using (diacetoxyiodo)benzene (PIDA) at room temperature, microwave irradiation, or tert-butyl nitrite (TBN) under reflux. Coumarin, isoxazole, and pyridine groups were selected for hybridization in one molecule due to their biological impact to inhibit lipid peroxidation and an enzyme implicated in inflammation. Preliminary in vitro screening tests for lipoxygenase (LOX) inhibition and anti-lipid peroxidation for the new hybrids were performed. A discussion on the structure-activity relationship is presented. Compounds 12b and 13a were found to be potent LOX inhibitors with IC50 5 μΜ and 10 μΜ, respectively, while 12b presented high (90.4%) anti-lipid peroxidation. Furthermore, hybrids 12b and 13a exhibited moderate-to-low anticancer activities on HeLa, HT-29, and H1437 cancer cells.

The metabolic cycle of L-proline plays a crucial role in cancer cell survival, proliferation, and metastasis. A key intermediate in the biosynthesis and degradation of proline is 3,4-dihydro-2H-pyrrole-2-carboxylic acid. A direct route for synthesizing substituted derivatives of this acid involves the cyclization of 2-amino-5-oxonitriles. Michael additions of [(diphenylmethylene)amino]acetonitrile to enones in a basic medium-either with aqueous sodium hydroxide or under solid-liquid phase-transfer catalysis conditions using CaO as a base-enable the synthesis of substituted 2-amino-5-oxonitriles as single diastereoisomers or as diastereoisomeric mixtures. Selective removal of the diphenylmethylene-protecting group, followed by in situ cyclization in acidic conditions, yields trans- and cis-3,5-diaryl-3,4-dihydro-2H-pyrrole-2-carbonitriles. The reaction of nitriles with HCl/dioxane/methanol followed by treatment with water produces esters and amides as by-products. In vitro screening of the synthesized compounds against multiple human cancer cell lines revealed that some compounds exhibit a good or high selectivity index. In conclusion, the synthetic schemes presented offer simple and efficient routes for the preparation of the derivatives of substituted 3,4-dihydro-2H-pyrrole-2-carboxylic acids, with some compounds exhibiting promising antiproliferative activity.

Glioblastoma (GBM) is one of the most invasive central nervous system tumors, with rising global incidence. Therapy resistance and poor prognosis highlight the urgent need for new anticancer drugs. Plant alkaloids, a largely unexplored yet promising class of compounds, have previously contributed to oncology treatments. While past reviews provided selective insights, this review aims to collectively compare data from the last decade on (1) plant alkaloid-based anticancer drugs, (2) alkaloid transport across the blood-brain barrier (BBB) in vitro and in vivo, (3) alkaloid mechanisms of action in glioblastoma models (in vitro, in vivo, ex vivo, and in silico), and (4) cytotoxicity and safety profiles. Additionally, innovative drug delivery systems (e.g., nanoparticles and liposomes) are discussed. Focusing on preclinical studies of single plant alkaloids, this review includes 22 botanical families and 28 alkaloids that demonstrated anti-GBM activity. Most alkaloids act in a concentration-dependent manner by (1) reducing glioma cell viability, (2) suppressing proliferation, (3) inhibiting migration and invasion, (4) inducing cell death, (5) downregulating Bcl-2 and key signaling pathways, (6) exhibiting antiangiogenic effects, (7) reducing tumor weight, and (8) improving survival rates. The toxic and adverse effect analysis suggests that alkaloids such as noscapine, lycorine, capsaicin, chelerythrine, caffeine, boldine, and colchicine show favorable therapeutic potential. However, tetrandrine, nitidine, harmine, harmaline, cyclopamine, cocaine, and brucine may pose greater risks than benefits. Piperine's toxicity and berberine's poor bioavailability suggest the need for novel drug formulations. Several alkaloids (kukoamine A, cyclovirobuxine D, α-solanine, oxymatrine, rutaecarpine, and evodiamine) require further pharmacological and toxicological evaluation. Overall, while plant alkaloids show promise in glioblastoma therapy, progress in assessing their BBB penetration remains limited. More comprehensive studies integrating glioma research and advanced drug delivery technologies are needed.

Compounds with thiosemicarbazide and semicarbazide scaffolds are among the most promising structures in medicinal chemistry due to the possibility of forming multiple hydrogen bonds. Therefore, six new derivatives of 4-fluorophenoxyacetylthiosemicarbazide and 4-fluorophenoxyacetylthiosemicarbazide were designed to compare their physicochemical properties, biological activity, and in silico pharmacokinetic parameters. All compounds were characterized by 1H, 13C NMR, 19F, IR spectra. For selected derivatives (AB2 and AB5), X-ray studies were performed to confirm their synthetic route and identify the tautomeric forms and intra- and intermolecular interactions occurring in the crystalline state. In the in silico pharmacokinetic study, a clear difference in lipophilicity was observed between thiosemicarbazide and semicarbazide derivatives. In vitro biological studies have shown the promising activity of thiosemicarbazides against prostate cancer cell line LNCaP, with a higher safety profile than semicarbazides. The most active compound AB2 showed IC50 = 108.14 μM against LNCaP. Based on biological studies, topoisomerase IIα was proposed as a potential molecular target, which was confirmed by molecular docking studies.

This review summarizes the research progress in the co-delivery of natural products (NPs) and small RNAs in cancer therapy. NPs such as paclitaxel, camptothecin, and curcumin possess multi-target antitumor effects, but their applications are limited by drug resistance and non-specific distribution. Small RNAs can achieve precise antitumor effects through gene regulation, yet their delivery efficiency is low, and they are prone to degradation by nucleases. Nanomaterial-based drug delivery systems (nano-DDSs) provide an efficient platform for the co-delivery of both, which can enhance the targeting of their delivery and improve the synergistic antitumor effects simultaneously. The mechanisms of the antitumor action of natural compounds and small RNAs, the design and application of nanocarriers, and the latest research progress in co-delivery systems are introduced in detail in this paper. The application prospects of the co-delivery of natural compounds and small RNAs in cancer therapy are also discussed.

Agrimonia pilosa Ledeb. (APL), a traditional Chinese herb frequently employed by Professor Zhou Zhongying, a master of traditional Chinese medicine, for colorectal cancer treatment, is rich in polyphenols with potential anti-tumor properties. To elucidate its bioactive components, this study developed a two-step purification process combining macroporous resin adsorption and liquid-liquid extraction to enrich polyphenols from APL (APLs). The adsorption/desorption mechanisms of APLs on macroporous resins were systematically investigated through resin screening, adsorption kinetics, and thermodynamics. The Langmuir isotherm model confirmed the adsorption process as spontaneous and exothermic. Pseudo-second-order kinetics effectively described the adsorption behavior of D101 resin. Optimized adsorption and column elution parameters were established, followed by liquid-liquid extraction for further purification. The components were compared and analyzed by ultra-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-Zeno-TOF-MS/MS). It was preliminarily identified that 29 polyphenols were mainly concentrated in water-saturated n-butanol (BEA) and ethyl acetate (ECA) extract fractions. Quantitative analysis using ultra-high performance liquid chromatography-triple quadrupole liquid chromatography-mass spectrometry (UHPLC-C-QTRAP-MS/MS) revealed higher contents of catechin (66.67 ± 1.33 ng·mg-1), hyperoside (382.56 ± 3.65 ng·mg-1), and chlorogenic acid (10.60 ± 0.05 ng·mg-1) in BEA compared to ECA (46.00 ± 2.00, 239.40 ± 2.60, and 3.42 ± 0.01 ng·mg-1, respectively). In vitro experiments demonstrated that BEA exhibited superior antiproliferative activity (IC50: 434.5 μg·mL-1) and significantly inhibited CT26 tumor cell migration compared to ECA (IC50: 672.5 μg·mL-1). The enhanced biological activity of BEA may be due to its higher polyphenol content, suggesting that these compounds mediate their anti-tumor effects through different biochemical pathways. This work lays the foundation for exploring the multi-target mechanism of anti-tumor effects of APLs.

This study investigates the synthesis, characterization, and cytotoxicity of dinuclear palladium(II) complexes with glycine (Pd1), alanine (Pd2), and methionine (Pd3) as ligands. UV-Vis and fluorescence spectroscopy were used to investigate the complexes' interactions with calf thymus DNA (CT-DNA) and bovine serum albumin. The obtained measurements demonstrate that Pd1 and Pd2 have stronger binding affinities for CT-DNA compared to Pd3, with Pd3 exhibiting the most significant cytotoxicity against the MDA-MB-231 cancer cell line. The binding behavior was quantified by calculating intrinsic binding constants (Kb) and Stern-Volmer constants (Ksv), showing that Pd1 and Pd2 interact more effectively with DNA, possibly due to less steric hindrance in their chelation. Cytotoxic activity was evaluated using an MTT assay, and the results confirm that Pd3, with methionine as the ligand, exhibited superior antitumor effects, inducing apoptosis through caspase-3 activation. The complexes also showed a strong affinity for BSA, indicating their potential for biological interaction. These discoveries shed light on the processes of palladium(II) complexes in biological systems, highlighting their DNA and protein-binding capabilities, as well as their anticancer potential. Further research is required to explore their pharmacokinetics and possible clinical applications.

Neuropilin-1 is henceforth a relevant target in cancer treatment; however, its way of action remains partly elusive, and the development of small inhibitory molecules is therefore required for its study. Here, we report that two small-sized neuropilin antagonists (NRPa-47 and NRPa-48), VEGF-A165/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in the triple-negative breast cancer cell line (MDA-MB-231). Nevertheless, NRPas exert a divergent pathway regulation of MAPK phosphorylation, such as JNK-1/-2/-3, ERK-1/-2, and p38β/γ/δ-kinases, as well as their respective downstream targets. However, NRPa-47 and NRPa-48 apply a common down-regulation of the p38α-kinase phosphorylation and their downstream targets, emphasising its central regulating role. More importantly, none of the 40 selected kinases, including SAPK2a/p38α, are affected in vitro by NRPas, strengthening their specificity. Taken together, NRPas induced cell death by the down-modulation of pro-apoptotic and anti-apoptotic proteins, cell death receptors and adaptors, heat shock proteins (HSP-27/-60/-70), cell cycle proteins (p21, p27, phospho-RAD17), and transcription factors (p53, HIF-1α). In conclusion, we showed for the first time how NRPas may alter tumour cell signalling and contribute to the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. Thus, the efficient association of NRPas and p38α-kinase inhibitor strengthened this hypothesis.

One of the most common strategies used in drug design is the molecular scaffold approach, which combines traditional medicine based on natural active compounds derived from plants with modern synthetic drug development. Designing new compounds based on natural skeletons enables extensive modifications of both bioavailability and biological activity. An excellent example of a natural molecular scaffold is the monoterpenes group, which serves as a core structure for building more complex molecules by attaching various chemical groups. Their ability to interact with biological targets, combined with structural versatility, makes them promising molecular scaffolds in pharmaceutical research and green chemistry applications. This review paper focuses on selected monoterpenes (carvacrol, carvone, citral, menthol, menthone, β-pinene, thymol, and verbenone), which are frequently used as molecular scaffolds. The newly designed derivatives exhibit various biological activities, including anticancer, antibacterial, antiviral, neuroprotective, and many others.

The Bcl-2 family's anti-apoptotic proteins, particularly Mcl-1, offer a viable avenue for cancer treatment since cancer cells can undergo apoptosis when their selective suppression occurs. Mcl-1 is essential for controlling the advancement of the cell cycle, as well as apoptosis. There is a constant clinical need for more potent treatments for breast and ovarian malignancies, even with advancements in the discovery of anticancer drugs. By synthesizing cyanopyrimidine derivatives that demonstrate both dual inhibitory activity against Mcl-1 and Bcl-2, and successful cell cycle arrest, our research seeks to contribute to the development of innovative therapeutic medicines. We created a number of new 6-substituted cyanopyrimidines and tested their anticancer effects on SKOV-3 and MCF-7 cell lines as well as apoptosis and cell cycle arrest assays.

Photodynamic therapy (PDT) has garnered significant attention as an effective and safe method for cancer therapy, with ongoing efforts to develop new photosensitizers to enhance its efficacy. This study aimed to develop novel photosensitizers with aggregation-induced emission enhancement (AIEE) properties. A series of 3-phenyl pyrano[4,3-b]quinolizine compounds (3-10) were synthesized by reacting pyrones (1a-e) with 2-pyridylacetate (2a) or 2-pyridylacetonitrile (2b) and then evaluated for their potential as photosensitizers. Spectroscopic analyses revealed that all compounds emitted blue to green fluorescence in ethanol, with emission wavelengths ranging from 446 nm to 515 nm. Compounds 5 and 6, lacking a substituent at position 5 of pyrano[4,3-b]quinolizine, exhibited AIEE behavior in aqueous solution. Furthermore, all compounds produced reactive oxygen species upon exposure to LED light. Notably, compounds 5 and 6 demonstrate high singlet oxygen (1O2) generation efficiency in water-rich solvents, where they tend to aggregate, contributing to their potential to destroy cancer cells. In vitro studies using human colon cancer cells (Colo205) demonstrated that 5 and 6 exhibited potent anti-tumor activity upon exposure to LED light. These findings suggest that compounds 5 and 6, based on 3-phenyl pyrano[4,3-b]quinolizine, possessing AIEE properties, are potential new photosensitizers for PDT.

Salvia aethiopis L. (Mediterranean sage) is a medicinal plant known for its rich phenolic content and different therapeutic properties. This study evaluated the phytochemical composition, antioxidant capacity and anticancer potential of water extracts from in vitro cultivated S. aethiopis. The extract exhibited a high total polyphenol (110.03 ± 0.7 mg GAE/g) and flavonoid (7.88 ± 0.25 mg QE/g) content, along with a strong oxygen radical absorbance capacity (an ORAC value of 3677.9 ± 24.8 µmol TE/g). LC-HRMS analysis identified 21 bioactive compounds, including salvianic acid C, rosmarinic acid, salvianolic acid K and various organic acids. A cytotoxicity evaluation using the Neutral Red Uptake assay showed that the extract had a low toxicity to non-cancerous BALB/3T3 cells. An antiproliferative activity assessment via the MTT assay revealed selective cytotoxicity against Hep G2 hepatocellular carcinoma cells (IC50 = 353.8 ± 21.8 µg/mL) and lung (A549) and prostate (PC-3) carcinoma cell lines. Migration assays and cytopathological evaluations confirmed the significant inhibition of cancer cell proliferation, the suppression of migration and G2/M cell cycle arrest. Flow cytometry revealed considerable increases in apoptotic and necrotic cell populations following treatment with S. aethiopis extract. These findings showed the potential of S. aethiopis as a promising source of bioactive compounds with antioxidant and anticancer properties, supporting its further exploration for therapeutic applications.

Addition of a CDK4/6 inhibitor to endocrine therapy (ET) prolongs survival in HR + /HER2-metastatic breast cancer (MBC). Gastrointestinal side effects, predominantly diarrhoea and abdominal pain, are common in patients receiving abemaciclib. This can potentially increase symptom burden, reduce quality of life (QoL) and affect treatment adherence. This longitudinal mixed-methods study with a 6-month follow-up explored patients' outcomes and experiences.

The IMPACTOR study (IMPact of AbemaCiclib on patienTs' rOles and Responsibilities-ISRCTN17281696) was developed to capture experiences of women with MBC being treated with abemaciclib in a real-world setting. The primary aim was to explore changes to quality of life over time and our secondary aim was to understand these changes in detail via qualitative interviews, as presented here.

In this study, we constructed a linear antibody-drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine pairs with different water-soluble substituents to further modify the linker and synthesized side-chain ADCs 7300-LP3004 and 7300-LP2004, modified by polysarcosine and polyethylene glycol, respectively. In vitro experiments showed that, after incubation at 55 °C in phosphate-buffered saline for 48 h, 7300-LP3004 aggregation was 45.24%, which was significantly lower than that of 7300-LP1003 (77.14%). Cell cytotoxicity assays demonstrated that the side-chain ADCs, 7300-LP3004 and 7300-LP2004, exhibited significantly higher activity (IC50 values of 39.74 nM and 32.17 nM, respectively) compared to the linear ADC and 7300-Deruxtecan (IC50 of 186.5 nM and 124.5 nM, respectively). In the subcutaneous model of SHP-77 NOD scid gamma mice, when the ADC dose was 5 mg/kg, 7300-LP3004 showed the highest tumor inhibition rate with a tumor growth inhibition (TGI) of 106.09%, which was superior to that of the positive control 7300-Deruxtecan, which had a TGI of 103.95%. In conclusion, 7300-LP3004 demonstrated strong antitumor activity and high physicochemical stability, highlighting the need for further research and development of ADC drugs.

Immune checkpoint inhibitors (ICIs) have significantly advanced cancer therapy, yet their efficacy in tumors with low tumor mutational burden (TMB) remains suboptimal. In this study, we aimed to elucidate the impact of somatic mutations on overall survival (OS) in TMB-low patients treated with ICIs and to explore the potential for personalized treatment selection through machine learning.

Background. Worldwide, colorectal cancer is the third most commonly diagnosed cancer. It is the second leading cause of cancer-related mortality. Recent studies establish a relationship between natural compounds from plants with the prevention and treatment of cancer. Specifically, glucosinolates with antitumoral capacity and polyphenols with the ability to scavenge free radicals that can cause cell damage have been identified in the Brassicaceae family. Objectives. Based on the previously mentioned factors, this study aimed to develop a nutraceutical made with extracts from different Brassicaceae seeds and study its antioxidant and antiproliferative action in vitro and in vivo using the AOM/DSS model in CC57BL6J mice. Results. Extract from the seeds of Eruca sativa and Sinapis alba showed the highest antioxidant capacity among the different species studied and were selected for nutraceutical formulation, which was potentially absorbable (73%) after an in vitro digestion process. In total, thirty compounds were identified in the nutraceutical that could be responsible for its antioxidant and tumoral prevention capacity. The intake of nutraceutical was a successful intervention to prevent the development of polyps by 31.6% and their size by 53.9%. When the nutritional intervention was used in combination with a physical exercise protocol, these parameters dropped to 52.3% and 62.6%, respectively. Conclusions. These findings suggest that the consumption of a diet rich in bioactive compounds from Brassica species, in combination with physical activity, is a valuable prevention strategy for colorectal cancer. However, more research is required to evaluate the efficacy and safety of these interventions in clinical settings.

Cancer medications can cause cardiac issues, which are difficult to treat in oncologic patients because of the risk of complications. In some cases, this may significantly impact their well-being and treatment outcomes. Overall, these complications fall under the term "drug induced cardiotoxicity", mainly due to chemotherapy drugs being specifically toxic to the heart, causing a decrease in the heart's capacity to pump blood efficiently and leading to a reduction in the left ventricular ejection fraction (LVEF), and subsequently possibly leading to heart failure. Anthracyclines, alkylating agents, and targeted therapies for cancer hold the potential of causing harmful effects on the heart. The incidence of heart-related issues varies from patient to patient and depends on multiple factors, including the type of medication, dosage, duration of the treatment, and pre-existing heart conditions. The underlying mechanism leading to oncologic-drug-induced cardiovascular harmful effects is quite complex. One particular group of drugs, called anthracyclines, have garnered attention due to their impact on oxidative stress and their ability to cause direct harm to heart muscle cells. Reactive oxygen species (ROS) cause harm by inducing damage and programmed cell death in heart cells. Conventional biomarkers alone can only indicate some degree of damage that has already occurred and, therefore, early detection is key. Novel methods like genetic profiling are being developed to detect individuals at risk, prior to the onset of clinical symptoms. Key management strategies-including early detection, personalized medicine approaches, and the use of novel biomarkers-play a crucial role in mitigating cardiotoxicity and improving patient outcomes. Identification of generated genetic alterations and the association to an increased likelihood of cardiotoxicity will allow treatment in a more personalized approach, aiming at decreasing rates of cardiac events while maintaining high oncological efficacy. Oncology drug-induced cardiotoxicity is managed through a combination of preventive strategies and therapeutic interventions from the union of cardiac and oncological knowledge.

Neoplastic disorders, particularly malignant carcinomas, are complex systemic diseases characterized by unregulated cellular proliferation, the invasion of adjacent tissues, and potential metastasis to distant bodily sites. Among the diverse spectrum of cancer subtypes, malignant melanoma is a highly aggressive form of cutaneous cancer originating in melanocytes, the pigment-producing cells resident in the skin. This malignancy is distinguished by its rapid and uncontrolled growth, as well as its propensity for metastasis to vital organs, thereby posing significant challenges to therapeutic intervention and prognostication. Early detection of melanoma is crucial for optimizing patient outcomes, as diagnosis at an advanced stage often yields a poor prognosis and limited treatment options. Diagnostic modalities for melanoma encompass comprehensive clinical evaluations by dermatologists; radiological imaging techniques such as ultrasonography, magnetic resonance imaging (MRI), computed tomography (CT) scans; and excisional biopsies for accurate histopathological assessment. Malignant melanoma is typically treated with surgery to remove the tumor, followed by immunotherapy to enhance the immune response, targeted therapy for tumors with specific genetic mutations, chemotherapy for advanced stages, radiation therapy to manage metastasis, and other adjunct therapies. This review presents the properties and possible adjunct therapeutic effects against malignant melanoma of quercetin found in the literature and explores, based on the observed physicochemical properties and biological activity, its potential development as a topical formulation for cutaneous application. Quercetin is a naturally occurring flavonoid compound abundant in various plant-based food sources, including apples, onions, berries, and citrus fruits, and has exhibited promising antiproliferative, antioxidant, and anticancer properties. Its distinctive biochemical structure enables quercetin to effectively neutralize reactive oxygen species and modulate key carcinogenic pathways, thereby rendering it a potential candidate for therapeutic intervention in managing malignant tumors, including melanoma.