In this study, twenty-four new furoxan and seco-coumarin hybrids were synthesized, and their antiproliferative activities against four breast cancer cells (MCF-7/ADR, MCF-7, MDA-MB-231, and MDA-MB-468) were evaluated. Among them, compound 9e exhibited significant toxicity against MCF-7/ADR cells compared to MCF-7 cells, with a 1401-fold increase, indicating its high collateral sensitivity. Meanwhile, 9e exhibited relatively lower toxicity to normal cell lines and improved solubility compared to the previous active compound, 4A93, which features a coumarin integrity core. Preliminary pharmacological studies revealed that 9e might be a potential P-glycoprotein substrate, which enters the lysosomes of MCF-7/ADR to release effective concentrations of nitric oxide, producing reactive oxygen species and inducing apoptosis. Moreover, laser confocal microscopy and Western Blot experiments showed that 9e could induce autophagy in MCF-7/ADR cells. Additionally, the anti-tumor activity of compound 9e could be inhibited by the ferroptosis inhibitor Fer-1. These results suggest that the remarkable antiproliferative potency of these hybrids in MCF-7/ADR may be related to multiple anticancer mechanisms. As a novel nitric oxide donor, compound 9e was used to explore the potential development of an anti-tumor candidate with special pharmacological mechanisms to overcome multidrug resistance in breast cancer.

The use of plant extracts and the compounds isolated from them for the treatment of cancer is an area of active research, given their therapeutic potential. This work focused on evaluating the literature related to the antiproliferative activity of extracts obtained from plants of the genus Tabebuia and molecules isolated in vitro or in vivo. For the search, MeSH and DECS terms were employed in the PubMed, Scopus, and SciELO databases. Research has shown that plant extracts derived from plants of the genus Tabebuia exhibit potential applications in the search for new molecules with antiproliferative activity. Among the isolated molecules, the most evaluated correspond to β-lapachone (naphthoquinone); however, molecules with antiproliferative potential belonging to groups such as iridoids, flavonoids, quinones, furanonaphthoquinones, triterpenes, and polysaccharides have also been isolated and reported. Additionally, synthesized molecules have been evaluated on the basis of the modifications made to the structures of molecules isolated from the plant extracts to increase their activity, aiming to develop more potent antitumor agents for future clinical use.

Photodynamic therapy (PDT) is a minimally invasive technique-used for the local eradication of neoplastic cells-that exploits the interaction of light, oxygen, and a photo-responsive drug called photosensitizer (PS) for the local generation of lethal ROS. Push-pull chromophores, that bear electron donor (D) and acceptor (A) groups linked through a π-electron bridge, are characterized by a non-homogeneous charge distribution in their excited state, with charge transfer from one extremity of the chain to the other one (Internal Charge Transfer-ICT). This phenomenon has a direct impact on the photophysical features of the push-pull compounds, as the bathochromic shift of the emission maxima and intersystem crossing (ISC) of the excited state are directly connected with the production of reactive oxygen species (ROS). In continuing our research regarding the synthesis and use of oligophenylene ethynylenes (OPEs) in PDT, two new push-pull glycosyl OPE-NOF and OPE-ONF-featuring electron-donor N,N-dimethylamino (N) and dimetoxyaryl (O) and acceptor tetrafluoroaryl (F) moieties on the OPE chain-have been efficiently prepared. The interchanged position of the D groups onto the conjugated skeleton was aimed to tune and optimize the push-pull effect, while the introduction of glucoside terminations was directed to give biocompatibility and bioaffinity to the chromophores. OPE-NOF, OPE-ONF, and the synthetic intermediates were fully characterized, and their photophysical properties were investigated by using UV-Vis absorption and emission spectroscopy. OPE-NOF showed a strong charge-transfer character and high PDT effect on HeLa cancer cells when irradiated with non-harmful blue light, causing massive cancer cell death.

Quercetin (QUE) is a bioactive flavonoid that is naturally present in various fruits and possesses many pharmacological activities. Despite its health benefits, the bioavailability of quercetin is relatively low due to its crystalline form and hydrophobic structure. An approach to overcoming these drawbacks is its incorporation into amorphous polymer matrices. PLA and PLA/PEG fibrous materials loaded with QUE were obtained by electrospinning. The XRD analysis revealed a visible decrease in the crystallinity of QUE after its incorporation into PLA and PLA/PEG fibers. The obtained fibrous materials and, especially, the PLA/PEG mat loaded with the flavonoid exhibited high antioxidant activity due to the better wettability and higher release rate of the bioactive compound. Moreover, the PLA/QUE and PLA/PEG/QUE mats possessed antibacterial properties against Staphylococcus aureus and Pseudomonas aeruginosa. Furthermore, the antitumor activity of the prepared mats was tested against SH-4 cancer cells and HaCaT keratinocytes. The obtained results reveal that the QUE-loaded fibrous mats exhibited high anticancer activity against cancer cells but lower toxicity to normal keratinocytes. The combined antioxidant, antibacterial and in vitro antitumor activities render these novel PLA-based materials loaded with QUE promising candidates for wound dressing applications and for application in local tumor treatment.

Leukemia is a malignant tumor of the hematopoietic system. Approximately 15% of adult leukemias are chronic myeloid leukemias (CMLs), and this incidence increases annually. The BCR-ABL oncoprotein drives the initiation, promotion, and progression of CML. Although tyrosine kinase inhibitors (TKIs) are first-line therapies for CML, BCR-ABL-mediated drug resistance limits their clinical efficacy and patient prognosis. Perillaldehyde (PAE), a monoterpene and primary volatile oil from perilla, is a promising small-molecule candidate for degrading BCR-ABL and has potential medical applications. The molecular mechanism showed that PAE regulated the expression of autophagy- and apoptosis-related proteins in K562 cells. Confocal laser observation showed that PAE damaged the mitochondrial membrane potential and induced ROS generation. Further evaluations indicated that PAE targeted HSP70 and inactivated the phosphorylation of BCR-ABL, thereby inhibiting its downstream proteins. This study may produce a lead compound for CML therapy as PAE may be an effective treatment for further exploration.

This study focuses on the extraction, characterization, and biological evaluation of diterpenes from green coffee beans, specifically, cafestol and kahweol. These compounds, known for their potential health benefits, were isolated via optimized extraction and saponification processes. Separation was achieved using silver nitrate-impregnated silica gel, and structural elucidation was performed through advanced 1D and 2D NMR techniques, including HSQC, HMBC, and (IN)ADEQUATE. Due to kahweol's instability, the research prioritized cafestol for the synthesis of rhodamine B conjugates. Initial ester-linked conjugates proved unstable, prompting the development of more robust derivatives through amide linkage strategies and further functionalization via acetylation and oxidation reactions. Some oxidation methods led to furan ring cleavage, impacting structural integrity. Selected compounds were tested for cytotoxicity using SRB assays on human tumor cell lines (MCF7, A2780) and non-malignant fibroblasts (NIH 3T3). While the parent diterpenes and many derivatives showed minimal activity, several cafestol-rhodamine B conjugates demonstrated notable cytotoxic effects. Compound 6, in particular, exhibited selective activity against cancer cells with reduced toxicity toward non-malignant cells.

Glioblastoma multiforme is a highly aggressive intrinsic brain tumor with a very poor survival rate. The main treatment for cancer is surgery combined with postoperative radiotherapy and temozolomide chemotherapy. Since the outcomes of treatment are unsatisfactory, the search for more effective drugs is crucial. Our previous study indicated that mephedrone, a synthetic cathinone, reduced neuron and astrocyte viability and oligodendrocyte proliferation. The aim of the present study was to investigate the effect of mephedrone on selected human glioblastoma (LN-18, LN-229, T98G) and human anaplastic astrocytoma (MOGGCCM) cell lines. The effects of mephedrone on cell viability and proliferation, DNA synthesis, cell cycle progression and the type of cell death were studied. Our results showed that mephedrone possesses potential anticancer activity. The viability and proliferation of all four human glioblastoma and human anaplastic astrocytoma cell lines used were decreased in a concentration-dependent manner. Studies conducted on LN-18 and T98G cells confirmed the significant antiproliferative properties of mephedrone, which reduced DNA synthesis and affected cell cycle progression. Microscopic evaluation supported the antiproliferative effect of the tested compounds. Moreover, substantial cytoplasmic vacuolization in the LN-18 cell line was revealed. This finding may indicate the potential of mephedrone in anticancer therapy.

Dodonaea viscosa (Sapindaceae), a Hawaiian local medicinal plant, has been traditionally used to treat rashes and skin diseases. The study aimed to discover and characterize bioactive compounds from D. viscosa flowers extract with antimicrobial and antitumor properties. Thirteen compounds were isolated from the methanol extract of D. viscosa flowers, and their structures were characterized using spectroscopy data, comparing their NMR spectroscopic profiles with previously reported data. Subsequent antibacterial assays revealed that one particular compound, 12, exhibited significant antimicrobial activity against Gram-positive bacteria. Notably, it demonstrated a minimum inhibitory concentration (MIC) of 2 μg/mL, indicating its potent antibacterial potential. In addition to antimicrobial properties, the isolated compounds demonstrated dose-dependent antiproliferative effects in breast cancer cell lines. Notably, inflammatory breast cancer (IBC) cell lines, a highly aggressive subtype, were more sensitive to compound 6, with IC50 values of 4.22 μM (BCX-010), 6.74 μM (SUM190), and 7.73 (SUM149), compared to non-IBC cell line. These findings highlight the dual antibacterial and anticancer potential of compounds from D. viscosa, emphasizing their promise as candidates for therapeutic development.

Aberrant glycosylation, especially sialylation, on cell surface is often associated with cancer progression and immunosuppression. Over-sialylation of stage-specific embryonic antigen-4 (SSEA-4) to generate disialylGb5 (DSGb5) was reported to trigger Siglec-7 recognition and suppress NK-mediated target killing. In this study, efficient chemo-enzymatic and programmable one-pot methods were explored for the synthesis of DSGb5 and related sialosides for assembly of glycan microarrays and evaluation of binding specificity toward Siglecs-7, 9, 10, and 15 associated with immune checkpoint inhibition. The result showed weak binding of DSGb5 to these Siglecs; however, a truncated glycolyl glycan was identified to bind Siglec-10 strongly with a dissociation constant of 50 nM and exhibited a significant inhibition of Siglec-10 interacting with breast cancer cells.

Breast cancer is a heterogeneous disease, and treatment resistance remains a critical challenge. Claudin-8 (CLDN8), a tight junction protein, has emerged as a potential indicator of therapeutic response and prognosis in breast cancer patients. In this study, we evaluated CLDN8 as a predictive biomarker and a potential therapeutic target. We analyzed CLDN8 gene expression in breast cancer patient cohorts to assess its association with clinical outcomes and response to therapy. We also established breast cancer cell models with altered CLDN8 expression to examine its effects on cell behavior and drug sensitivity. High CLDN8 expression was significantly associated with improved disease-free survival, particularly in estrogen receptor-negative patients (p = 0.007), suggesting a favorable prognostic role. Notably, tumors with elevated CLDN8 showed better outcomes in patients treated with surgery alone or endocrine therapy, whereas in those receiving chemotherapy (including neoadjuvant) or anti-HER2 therapy, high CLDN8 levels were paradoxically linked to poorer survival and therapy resistance. In vitro, CLDN8 knockdown reduced sensitivity to endocrine treatments, HER2-targeted agents, and chemotherapeutic drugs, mirroring clinical patterns. In conclusion, our findings identify CLDN8 as an important prognostic factor in breast cancer and as a novel predictor of treatment response. These results underscore the potential utility of CLDN8 status in guiding personalized therapy and highlight CLDN8 as a candidate target for overcoming treatment resistance in breast cancer.

The tetrahydro-β-carboline heterocycle is a privileged scaffold found in numerous natural products and bioactive drugs, demonstrating significant potential for cancer therapy. In this study, we designed and synthesized 33 novel tetrahydro-β-carboline derivatives (2-34) based on this core structure and evaluated their anticancer activity against human lung cancer (A549). Among them, compounds 8 and 16 exhibited potent cytotoxicity against A549 cells, effectively suppressing cell migration and colony formation. Mechanistic studies revealed that these compounds promoted apoptosis by upregulating pro-apoptotic Bax, downregulating anti-apoptotic Bcl-2, and activating caspase proteins. Molecular docking and dynamics simulations demonstrated that compounds 8 and 16 form stable complexes with the Eg5 protein through multiple hydrogen bonds, which was further validated by thermal shift assays. Collectively, these findings indicate that compounds 8 and 16 induce apoptosis in A549 cells by selectively targeting and stabilizing Eg5, highlighting their potential as lead candidates for lung cancer therapy.

Immunotherapy has significantly changed the treatment paradigm for solid tumors, with immune checkpoint inhibitors now established in the management of many malignancies. Despite initial success, durable responses remain limited to a subset of patients, often less than 30%, due to both intrinsic and acquired resistance mechanisms. These challenges have prompted the development of next-generation immunotherapies. Recent efforts have expanded the scope of immunotherapy beyond PD-1/PD-L1 and CTLA-4 inhibition, focusing on new immune targets currently under investigation in early phase clinical trials. These include novel immune checkpoint inhibitors, immunomodulators targeting the tumor microenvironment, and bispecific antibodies. This review provides a comprehensive overview of emerging immune targets currently being investigated in early drug development, discussing their mechanisms of action, preliminary clinical outcomes, and potential future directions.

Multidrug resistance (MDR) poses a significant challenge in cancer therapy, often leading to treatment failure and relapse. ATP-binding cassette (ABC) transporters, particularly ABCG2, play a pivotal role in MDR development by actively expelling chemotherapeutic agents from cancer cells. This study investigates the effects of two groups of primaquine derivatives-fumardiamides (1a-d) and bis-ureas (2a, b), both bearing halogenated benzene rings-on the activity of P-glycoprotein (P-gp) and ABCG2. Their potential to reverse MDR was evaluated through a series of functional assays aimed at comparing transporter-compound interactions. The results indicated that fumardiamide derivatives, specifically 1a, 1b, and 1d, exhibited potent inhibition of ABCG2 while having no effect on P-gp, demonstrating a selective mode of action. The tested derivatives displayed low to moderate cytotoxicity and did not affect ABCG2 expression or localization. Moreover, these compounds enhanced the sensitivity of drug-resistant cancer cell lines to mitoxantrone, underscoring their potential to overcome ABCG2-mediated MDR. These findings suggest that chemical modifications of primaquine, particularly the incorporation of fumardiamide moieties, confer novel biological properties, providing promising leads for the development of selective ABCG2 inhibitors.

Autophagy plays a central role in cellular degradation and recycling pathways involving the formation of autophagosomes from cellular components. The Atg8 protein family, particularly LC3, is essential to this process, and dysregulation has been implicated in many diseases (including cancer). Furthermore, therapeutic strategies targeting Atg8 proteins like LC3 can be advanced by exploiting the expanding knowledge of the "LC3 interacting region" (LIR) domain to develop inhibitory ligands. Here, we report a computational approach to design novel peptides that inhibit LC3B. The LIR domain of a known LC3B binder (the FYCO1 peptide) was used as a starting point to design new peptides with unnatural amino acids and conformational restraints. Accomplishing molecular dynamics simulations and binding free energy calculations on the complex of peptide-LC3B, new promising FYCO1 analogs were selected. These peptides were synthesized and investigated by biophysical and biological experiments. Their ability to affect cellular viability was determined in different cancer cell lines (prostate cancer, breast cancer, lung cancer, and melanoma). In addition, the ability to inhibit autophagy and enhance the apoptotic activity of Docetaxel was evaluated in PC-3 prostate cancer cells. In conclusion, this research presents a rational approach to designing and developing LC3B inhibitors based on the FYCO1-LIR domain. The designed peptides hold promise as potential therapeutic agents for cancer and as tools for further elucidating the role of LC3B in autophagy.

In this article, the synthesis and characterization of chlorin-based photosensitizers for potential applications in photodynamic therapy (PDT) of triple-negative breast cancer (TNBC) are described. The photodynamic efficacy of the synthesized chlorin-desthiobiotin (CDBTN) conjugate and its zinc and indium complexes were compared with the starting unconjugated precursor methyl pheophorbide, and assessed in a TNBC cell line in vitro. The chlorin-desthiobiotin complex aims to target the vitamin receptors upregulated in malignant cancer cells. The synthesized CDBTN was combined with chemotherapeutic agents (paclitaxel, cisplatin or fluorouracil) to evaluate their binary photodynamic efficacy. Cell survival assay in vitro indicated that the chlorin-vitamin conjugate CDBTN-alone and in combination with paclitaxel or fluorouracil-is photoactive against the TNBC cell line, but not when combined with cisplatin. The combination index (CI) calculated using the Chou-Talalay method indicated synergism of CDBTN and fluorouracil combination, aligning with the in vitro assay. The photodynamic cytotoxicity of CDBTN was also evaluated in vivo using the hydra as a novel model organism. This study is the first to show the use of the aquatic hydra organism in assessing photodynamic activity of the photosensitizer alone or in combination with chemotherapeutic agents. In vivo results with hydras indicated that the CDBTN-cisplatin combination is more phototoxic than CDBTN-paclitaxel or CDBTN-fluorouracil binary treatment. With the proper adjustment of concentration and light dosage, the synthesized photosensitizer can provide promising application in binary chemotherapy PDT treatment of TNBC.

Silver nanoparticles (AgNPs) have emerged as promising agents in cancer diagnostics and/or therapy, demonstrating a lot of possible pharmacological actions. However, understanding the pharmacokinetics and safety profiles of nanoparticles, which is crucial for their clinical application, still raises many questions. Studies indicate that AgNPs can accumulate in tumour tissues, improving drug delivery and specificity. However, their interaction with biological systems necessitates thorough safety evaluations. Classical methods for assessing AgNPs' safety include cytotoxicity assays, genotoxicity tests, and histopathological examinations. However, novel techniques are emerging, such as advanced imaging and biomarker analysis, offering more precise toxicity assessments. Prediction models, including computational simulations and in silico analyses, are being developed to forecast AgNPs' toxicity profiles. These models aim to reduce reliance on animal testing and expedite the evaluation process. To mitigate potential risks associated with nanoparticle-based therapies, strategies such as surface modification, controlled release systems, and targeted delivery are being explored. These methods aim to enhance therapeutic efficacy while minimizing adverse effects. The main aim of this review article is to describe AgNPs from the point of view of their pharmacokinetic/toxicokinetic profile in the light of modern knowledge. Special attention will be given to novel methods for assessing the safety and toxicity profiles of AgNPs, providing insights into their interactions with cancer therapies and their potential clinical applications.

Anticancer drug design has been reformed by the creation of heterocyclic hybrids. The introduction of a quinoline scaffold affects the activity, toxicity, and bioavailability of new compounds. The aim of this study was to synthesize and evaluate the biological activity of hybrids of 1,4-naphthoquinone with the 8-hydroxyquinoline moiety. The structure of the new compounds was characterized using spectroscopic methods, such as HR-MS, NMR, and IR. The analysis was supplemented by calculated NMR and IR spectra. The physicochemical properties and bioavailability of the compounds were examined using in silico methods. An analysis of reactivity descriptors showed that the compounds are good electron acceptors and exhibit high reactivity. Bioavailability properties confirm that hybrids could be good oral administration drugs. The biological potential of hybrids was examined by designation of the enzymatic conversion rate of the NQO1 protein and in vitro against cancer cell lines with overexpression of the gene encoding the NQO1 protein. The possibility of interaction between the tested ligand and the NQO1 protein was examined by molecular docking methods.

Colon cancer is the second leading cause of cancer-related deaths in the world. This is commonly observed among older adults, and the occurrence of colon cancer is mainly influenced by unhealthy lifestyle factors. Edible medicinal mushrooms have been demonstrated to have anti-colon cancer effects both individually and in combination with conventional therapies, including synergistically enhancing the efficacy of chemotherapy medications such as 5-fluorouracil in preclinical models. Medicinal mushrooms such as Lentinus edodes, Phellinus linteus, Ganoderma lucidum, Inonotus obliquus, Pleurotus ostreatus, Hericium erinaceus, Pleurotus eryngii, Gloeostereum incarnatum, and Termitomyces heimii are emerging as promising candidates, not only because conventional treatments for colon cancer face significant limitations, including side effects, psychological impacts on patients, high cost, limited specificity toward cancer and healthy cells, and the development of drug resistance, but also due to the diverse array of bioactive compounds present within them. Therefore, there is a strong demand for innovative, affordable, and minimally invasive treatments such as medicinal mushrooms. Their bioactive compounds, including terpenoids, sterols, phenols, polysaccharides, acids, sesquiterpenes, alkaloids, lactones, metal-chelating agents, nucleotide analogs, glycoproteins, β-glucan, cerebrosides, steroids, terpenes, quinolones, anthraquinones, benzoic acid derivatives, linoleic acid, ascorbic acid, glycosides, organic acids, flavonoids, grifolin, tocopherols, proteins, indoles, lectin, and laccases, exert anti-colon cancer activities through various mechanisms, including anti-proliferative effects, cell cycle arrest, anti-inflammatory effects, antioxidant effects, induction of apoptosis, cytotoxic effects, and antimigratory effects. Further research is needed to elucidate the molecular mechanisms and confirm the safety and efficacy of medicinal mushrooms as a holistic anti-colon cancer treatment.

Formononetin is widely used in anti-tumor research, but its poor water solubility leads to low absorption and poor utilization efficiency in vivo, limiting further development. The triphenylphosphine cation was partially attached to the 7-position hydroxyl group of formononetin to specifically target it into the mitochondria of tumor cells to enhance the anti-tumor effect. Detailed structural characterization via 1H-NMR and 13C-NMR analysis confirmed the physical properties and chemical structures of 21 newly synthesized derivatives. The effects of these derivatives on tumor cells were assessed by in vitro and computational methods. MTT results from four tumor cell lines showed that formononetin derivatives containing triphenylphosphine had stronger anti-tumor activity than formononetin and exhibited more cytotoxic effects in cancer cells than in normal cells. In particular, the final product 2c (IC50 = 12.19 ± 1.52 μM) showed more potent anti-tumor activity against A549 cells. It was also superior to formononetin and 5-FU. To identify the potential biological targets, the core-expressed gene SHMT2 in lung cancer mitochondria was screened using network pharmacology technology, and molecular docking analysis confirmed the stable binding of the end products to the amino acid residues of the core genes through the formation of hydrogen bonds and via other interactions. In addition, molecular docking simulations further confirmed that the end product exhibited excellent stability when bound to SHMT2. These results suggest that triphenylphosphine-containing formononetin derivatives are worthy of further exploration in the search for novel drug candidates for the treatment of cancer.

The aim of this study was to investigate the effect of Ostwald ripening inhibitors on D-limonene (D-LMN) nanoemulsions and to elucidate their impact on oral cancer cells. Various inhibitors, including olive oil, soybean oil, and perilla oil, were incorporated into D-LMN nanoemulsions at different ratios (25:75-75:25, D-LMN to inhibitor). The resulting nanoemulsions were evaluated for droplet size, size distribution, zeta potential, stability, droplet morphology, cytotoxicity, antimetastatic and anti-invasive activities, apoptosis induction, and cell cycle arrest. Results showed that the 75:25 D-LMN to inhibitor ratio produced the smallest droplet size and exhibited great stability, particularly with perilla oil. Notably, D-LMN nanoemulsions displayed strong anti-oral cancer effects by reducing cell viability, metastasis, and invasion. Apoptosis was induced, as evidenced by nuclear fragmentation, Annexin V binding, and altered expression of BAX, BCL-XL, Cytochrome c, and Caspase-9. Additionally, the nanoemulsions caused cell cycle arrest via downregulation of Cyclin D1, CDK2, CDK4, and CDK6. These findings highlight the potential of D-LMN nanoemulsions as a promising alternative therapeutic strategy for oral cancer treatment.