Background and Objectives: Osteosarcoma is a primary malignant bone tumor characterized by the proliferation of malignant mesenchymal cells and primarily affects children and adolescents. Hesperidin (Hes) interacts with various cellular targets and inhibits cancer cell proliferation by inducing apoptosis. However, the precise mechanisms underlying Hes-induced cell death in osteosarcoma cells remain unclear. This study aimed to investigate the effects of Hes and cisplatin (Cis) on the Bax/Bcl-2 apoptotic pathway in osteosarcoma cells. Materials and Methods: The human osteosarcoma cell line U2OS (Uppsala 2 Osteosarcoma) was treated with IC50 concentrations of Hes and Cis for 48 h. Changes in the mRNA expression levels of Bax, Bcl-2, Caspase-3, and Survivin-key regulators of apoptosis-were analyzed using quantitative real-time PCR (qPCR). The synergistic and/or antagonistic interactions of the Hes and Cis combination were evaluated using Combenefit v2.021 software (Cambridge, UK). Results: The dose-response curve for Hes revealed a gradual reduction in cell viability, with an IC50 value of 106 µM, while the IC50 value for Cis was 4.83 µM. The levels of the inflammatory cytokines IL-1β, TNF-α, and IFN-γ were significantly decreased in the treatment groups compared to the control (p = 0.01). IL-6 levels also showed a marked decrease, particularly in the Hes and Cis groups, with high statistical significance (p = 0.002). Treatment with Hes and Cis significantly upregulated the mRNA expression of Bax and Caspase-3, while significantly downregulating Bcl-2 and Survivin mRNA levels (p < 0.05). Notably, Bax expression was highest in the Hes + Cis combination group. The combination treatment exhibited enhanced cytotoxicity, especially at higher concentrations, indicating a synergistic effect between the two compounds. Conclusions: This study is the first to demonstrate that Hes induces apoptosis in U2OS osteosarcoma cells and that its combination with Cis may enhance anticancer efficacy by activating apoptosis-related cell death pathways. Given the growing focus on combination therapies and cell death mechanisms in cancer research, these findings provide valuable insights into potential novel strategies for osteosarcoma treatment.

This paper presents the influence of acetylation on the cytotoxic and antioxidant activity of natural triterpenes. Oleanolic acid, betulin, betulinic acid and other triterpenes have been modified to improve their pharmacological properties. Acylation of the hydroxyl group at the C-3 position showed significant changes in biological activity, in particular against cancer cell lines such as HeLa, A-549, MCF-7, PC-3 and SKOV-3, with the highest IC50 results for acetyloleanolic acid (1b) and acetylbetulinic acid (4b). Docking results showed that all compounds tested demonstrated the ability to bind to pockets (C1-C5) of the p53 Y220 protein, obtaining different Vina score values. The strongest binding was observed for compound 2b in the C3 pocket (-10.1 kcal × mol-1), while in the largest C1 pocket, the best result was achieved by compound 5b (-9.1 kcal × mol-1). Moreover, antioxidant studies using the CUPRAC and DPPH tests showed significant differences in the mechanisms of action of the compounds depending on the structure. The analyses of ADMETox confirmed the favorable pharmacokinetic profile and low toxicity of most of the tested derivatives. The results suggest that acetylated triterpenes, especially 1b and 4b, have great potential as anticancer drug candidates, requiring further research on their cytotoxic activity and structural modifications.

Aromathecin compounds-which contain the same indolizine core structure as camptothecin-like compounds-are expected to show anticancer activity. Among them, 22-hydroxyacuminatine-which has a substituent on the E-ring of the pentacyclic scaffold-exhibits topoisomerase 1 inhibitory activity; therefore, the development of efficient methods for its synthesis has been actively pursued. Herein, we report a versatile synthetic methodology for introducing various substituents on the E-ring, leading to the total synthesis of 22-hydroxyacuminatine as a model compound of the aromathecin family. The synthesis comprises the following key steps: the synthesis of an isoquinoline N-oxide via the thermal cyclization of 2-alkynylbenzaldehyde oxime, the subsequent Reissert-Henze-type reaction to yield an isoquinolone, and the construction of the indolizine moiety (CD-ring) through C-N bond formation via the Mitsunobu reaction. Consequently, a pentacyclic benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one framework is obtained. Using this methodology, the total synthesis of the natural products norketoyobyrine and naucleficine and an intermediate of the latter, which are indoloquinolizidine-type alkaloids, was achieved, and their antiproliferative activity against HCT-116 human colon cancer cells and HepG2 human liver cancer cells was assessed. Naucleficine and its intermediate exhibited moderate antiproliferative activity against HCT-116 cells, with IC50 values of 55.58 and 41.40 μM, respectively.

Non-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2-35%), HER2 gene amplification (2-20%), and gene mutations (1-4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only in 2004 that HER2 mutations were identified, and they currently represent a key druggable target in NSCLC. Despite numerous strengths, there is only one FDA/EMA-approved targeted therapy, an antibody-drug conjugate (ADC) called trastuzumab deruxtecan for pretreated patients with HER2 mutant NSCLC. In the first-line treatment, the standard of care (SoC) remains chemotherapy with or without immunotherapy. In the past, pan-HER tyrosine kinase inhibitors (TKIs) were extensively studied with poor results. But, two newly developed HER2-specific TKIs with low EGFR WT inhibition (BAY2927088 and zongertinib) reported encouraging results and received the breakthrough therapy designation from the FDA. Ongoing clinical trials are investigating new agents. This review focuses on HER2 alterations. Additionally, the anti-HER2 therapies explored so far will be discussed in detail, including the following: HER2 inhibitors (pan-inhibitors and selective inhibitors), monoclonal antibodies (mAbs), and ADCs. A section of this paper is dedicated to the role of immunotherapy in HER2-altered NSCLC. The last section of this paper focuses on the drugs under development and their challenges.

Several new amino-substituted aza-acridine derivatives bearing one or two basic side chains have been designed and synthesized. Their anticancer activities were evaluated in vitro against two human cancer cell lines: T24 (urothelial bladder carcinoma, malignancy grade III) and WM266-4 (metastatic melanoma). Some of the synthesized compounds induced significant antiproliferative effects, with WM266-4 cells appearing more susceptible than T24 cells. This apparent cell-type selectivity may reflect differences in the mutational profiles and molecular target landscapes between the two cancer models. A stability study under hydrolytic conditions, based on a validated method, indicated that the most active compounds were stable under aqueous conditions. Computational analysis further supported the stability of these analogs, providing insights into the structure-stability relationships of the synthesized compounds.

Head and neck squamous cell carcinoma (SCC), particularly in the oral cavity, is among the most prevalent and lethal forms of cancer globally. Current therapeutic strategies, predominantly involving cisplatin, face challenges like chemoresistance and toxicity to normal cells, justifying the exploration of new approaches. This study evaluates the antitumor, antiproliferative, and immunomodulatory potential of a synthetic peptide derived from IsCT1 (Isalo scorpion cytotoxic peptide), named AC-AFPK-IsCT1, in combination with cisplatin in oral squamous cell carcinoma cellular models. Tumor and normal cells were treated with varying concentrations of cisplatin and peptide, and the cytotoxicity was measured through an MTT assay, while apoptosis and cell cycle alterations were assessed via flow cytometry. Interestingly, the combination of AC-AFPK-IsCT1 with cisplatin exhibited higher specificity for tumor cells, significantly reducing IC50 values compared to cisplatin used as a single agent. Moreover, the combination treatment induced pronounced S-phase cell cycle arrest and enhanced apoptotic activity, evidenced by the upregulation of caspase-3, caspase-8, and p53, while maintaining low toxicity in normal fibroblast cells. The peptide also modulated the mitochondrial membrane potential, further contributing to the activation of intrinsic apoptotic pathways. The data suggest that AC-AFPK-IsCT1 potentiates the antitumor effects of cisplatin by engaging both intrinsic and extrinsic apoptotic pathways while preserving normal cell viability. These findings underscore the potential of combining cisplatin with AC-AFPK-IsCT1 as a promising therapeutic strategy for improving the efficacy of chemotherapy in SCC, reducing systemic toxicity, and overcoming chemoresistance.

To address the clinical challenges posed by symbiotic drug-resistant bacterial infections and tumor microenvironments, this study designed and synthesized novel carbazole/benzindole-based photosensitizers A1-A4, systematically evaluating their antitumor and antibacterial therapeutic potential through chemo-photodynamic therapy. Especially, compound A4 demonstrated potent Type I/II reactive oxygen species (ROS) generation capabilities. In vitro experiments revealed that A4 concentration-dependently inhibited HT-29 cells under hypoxic conditions (IC50 = 0.89 μM) with a prominent photodynamic index (PI > 9.23), and substantially promoted cancer cell programmed death. In antibacterial evaluations, A4 achieved the complete eradication of dermal MRSA infections within 7 days through ROS-mediated membrane disruption under illumination. In the HT-29 xenograft model, the PDT-chemotherapy synergy strategy achieved a tumor suppression rate of 96%. This work establishes an innovative strategy for the combinatorial management of multidrug-resistant infections and solid tumors.

Ferruginol, tanshinones and carnosol are considered privileged natural products due to their demonstrated diverse biological activities with relevance to cancer research. Globally, cancer continues to be a major contributor to mortality rates, making these compounds potentially valuable molecular scaffolds for further development as potential anticancer agents. In this work, a focused library of ferruginol, tanshinone IIA, and carnosol analogues was studied to examine their effectiveness against various solid tumor models. The compounds were efficiently synthesized from either methyl 12-hydroxy-dehydroabietate or 12-hydroxydehydroabietylamine in 1-3 step processes with good chemical yields. The compounds that were synthesized underwent a methodical evaluation using multiple biological tests (including viability assays, clonogenic assays, and mitochondrial membrane polarization measurements) to determine their ability to inhibit in vitro the growth of three breast cancer cell linages. It was determined that while most compounds exhibited biological activity, compounds 10 and 11 demonstrated significant efficacy against triple negative breast cancer cells. These compounds continue to show promising biological activity, suggesting that additional studies to understand their mechanisms of action would be valuable.

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound 3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide (10e) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by 10e was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound 10e interacted with IDO1 and HDAC6. Moreover, compound 10e was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound 10e also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents.

Cancer remains one of the leading causes of morbidity and mortality worldwide, driving the search for innovative and selective therapeutic agents. Topoisomerases I and II are essential enzymes involved in key cellular processes such as DNA replication and transcription. They have emerged as valuable anticancer targets; thus, many inhibitors of topoisomerases have been designed and some of them are considered to be major anticancer agents such as anthracyclines, etoposide or irinotecan. A great deal of attention is currently being paid to chalcones, a class of naturally occurring compounds, since they exhibit a wide range of biological activities, including anticancer properties. These compounds are characterized by an open-chain structure and an α,β-unsaturated carbonyl moiety that enables interaction with cellular targets. Recent studies aiming to design anti-topoisomerase agents have identified both natural and synthetic chalcones, including chalcone-based hybrids. This review highlights the structural diversity of chalcones as topoisomerase inhibitors and particular attention is given to structure-activity relationship studies and molecular hybridization strategies aimed at optimizing the pharmacological profile of chalcones. These findings underline the potential of chalcones as promising scaffolds in the design of next-generation anticancer agents.

Cervical cancer remains a leading cause of malignancy among women globally, disproportionately affecting women from low-to-middle-income countries, including South Africa. The high prevalence in impoverished communities places significant pressure on the public healthcare system. In these regions, human papillomavirus (HPV); the primary risk factor for cervical cancer-along with co-occurring immunosuppressive conditions such as HIV, is common. Compounding this burden is the widespread development of treatment resistance to conventional therapies like cisplatin and carboplatin. Resistance is frequently associated with therapy-induced cellular senescence, underscoring the need for more personalised treatment strategies tailored to individual patient profiles.

Histone deacetylases (HDACs) could regulate gene expression, arrest the cell cycle, alter epigenetics, promote angiogenesis, and evade cancer cell survival and apoptosis. HDAC inhibitors could act on cancer cells through multiple mechanisms, primarily by regulating gene expression, inducing cell-cycle arrest, promoting apoptosis, inhibiting angiogenesis, enhancing the immune response, and modifying the epigenome, representing valuable chemical entities for cancer therapy. The benzamide derivatives can chelate with the zinc ion at the active site of HDACs, interact with the surrounding amino acid residues in the active site cavity of HDACs, and cause conformational changes in HDACs. Accordingly, benzamide derivatives are useful HDAC inhibitors, and the benzamide-containing HDAC inhibitors have the potential to demonstrate robust anticancer activity. The purpose of this review is to summarize the current scenario of benzamide-containing HDAC inhibitors with anticancer therapeutic potential developed since 2020 to facilitate further rational exploitation of more effective candidates.

Compared with conventional anticancer strategies, targeted therapy and drug delivery systems offer several benefits that enhance treatment efficacy, safety, and precision. However, their efficacy can be significantly constrained by the lack of suitable molecular targets, stability and drug release issues, financial burden, and potential drug-related toxicity. Bioelectricity plays a fundamental role in maintaining cellular homeostasis. Ion channels are key factors in regulating cellular bioelectricity, and pharmacological manipulation of these proteins has emerged as a promising anticancer strategy. In this study, we evaluated the effectiveness of a Smart Injectable Hydrogel as a delivery system for the Kv11.1 potassium (K+) activator molecule NS1643 (SIHD-Ka) in inhibiting cancer growth. SIHD-Ka consists of an injectable chitosan/pluronic hydrogel encapsulating NS1643. Our in vitro and in vivo experiments demonstrated that SIHD-Ka facilitates the sustained release of NS1643 at a constant rate under physiological conditions (37 °C) and effectively inhibits tumor growth in a triple-negative breast cancer (TNBC) model without eliciting notable adverse effects. These findings indicate that SIHD-Ka is a promising platform for the localized and controlled delivery of K+ channel activators, offering a targeted therapeutic strategy for the treatment of cancers.

Epothilones were designated as one of the most recognized chemotherapeutic agents towards the drug-resistant tumors, for their higher potency to bind and stabilize the β-tubulin arrays, stopping the cell cycle. Epothilones were chemically resolved from Aspergillus fumigatus # MN744705.1, that being more affordable source than Sorangium cellulosum, for its rapid growth and unique biological behaviour. So, the aim of this work was to emphasize the chemical identity and efficacy of Aspergillus fumigatus Epothilone. The Epothilone structure of A. fumigatus was determined by HPLC, FT-IR, LC-MS analyses, with 507.7 m/z, compared to the authentic one of S. cellulosum. Aspergillus fumigatus epothilone B had the highest activity against HepG-2 (IC50 value 6.3 μM), and HCT-116 and Pc3 (IC50 value 7.4 μM), compared to Vero cells (18.7 μM) with selectivity index 2.9, 2.5, and 2.47, respectively. The anti-tubulin polymerizing potency of the purified Epothilone was about two folds more than Taxol, with an obvious resilient arrest to the cellular growth of the cells of HepG-2 at G2/M phase. The total, early and late apoptosis of the HepG2 cells were increased by 26.5%, 15.9% and 7.6%, respectively, with the epothilone of A. fumigatus, with an overall increase of apoptosis by 12 folds, compared to control. The caspase-9 and 3 activities were increased by 4 folds and 2.5 folds, with the Epothilone B, as revealed from the colorimetric activity and gene expression analyses. The level of released LDH of HepG-2 cells was increased exponentially with the Epothilone concentration, ensuring their negative effect on the plasma membrane permeability. From the docking results, the binding energy of Epothilone B with the tubulin-β was -9.96 kcal/mol, that was lower than Taxol (-7.87 kcal/mol), ensuring the higher affinity of Epothilone B to bind with the β-tubulin protein.

Herein, we report a new modified nanoprecipitation method for the fabrication of water-dispersible Poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating three poorly water-soluble anticancer agents as model drugs: paclitaxel (PTX), docetaxel (DTX) or curcumin (Cur). These nanoparticles were water dispersible with favourable size for anticancer applications (below 200 nm) and relatively high drug loading (6.3-8.9%). These nanoparticles were stable for four weeks in solid state and up to 48 h when dispersed in water. PTX and Cur nanoparticles showed a very minimal release of the payload during a 72-h in vitro release study. The new method also yielded reproducible results across three different batches of each type of nanoparticles and following three times upscaling of PTX nanoparticles. PTX and Cur nanoparticles were more effective than the free drugs against MDA-MB-231 cells (p < 0.05). In addition, PTX nanoparticles showed a significant enhanced induction of early apoptosis in MDA-MB-231 cells (42.3%) in comparison to free PTX (23.7%, p < 0.05). Both flow cytometry and confocal microscopy confirmed the uptake of the nanoparticles by MDA-MB-231 cells. In conclusion, our modified nanoprecipitation method produces PLGA nanoparticles loaded with different anticancer agents and suitable for cancer therapy.

Alkaline hydrolysis of the crude resin glycoside fraction from the leaves and stems of Ipomoea lacunosa L. (Convolvulaceae) yielded organic acid and glycosidic acid fractions. The organic acid fraction included n-decanoic and n-dodecanoic acids. Acidic hydrolysis of the glycosidic acid fraction yielded 3 monosaccharides (d-glucose, d-fucose, and l-rhamnose) and 2 known hydroxyl fatty acids (11S-hydroxytetradecanoic and 11S-hydroxyhexadecanoic acids). Treatment of the glycosidic acid fraction with trimethylsilyldiazomethane (in hexane) afforded 1 new glycosidic acid methyl ester (lacunosinic acid J methyl ester) and 6 known glycosidic acid methyl esters. Eight new resin glycosides (lacunosins V-XII) were isolated from the leaves and stems, along with 2 known resin glycosides. Their structures were determined using spectroscopic and chemical analyses. Three types of resin glycosides were identified: those with 18-membered macrolactone, those with 19-membered macrolactone, and those with non-macrolactone structures. All these compounds contained n-decanoic and n-dodecanoic acids as the organic acid components. Nine of the isolated resin glycosides were tested for cytotoxic activity against HL-60 human promyelocytic leukemia cells. One compound exhibited activity with an IC50 value of 44.5 μM, while 3 compounds demonstrated moderate activity, with inhibition rates ranging from 53.5 to 68.7% at a concentration of 200 μM. In contrast, the remaining 5 compounds showed negligible effects even at 200 μM.

Triple M Overlap Syndrome is an ultra-rare and seldom-described immune-related adverse event (irAE) secondary to pembrolizumab therapy. This entity and its namesake are due to auto-immune phenomena involving myocardium, striated muscle and neuromuscular junction, yielding a syndrome of myocarditis, myositis and myasthenia gravis. Since it was first identified in 1975, only 100 cases of this syndrome are found in the literature. With the increasing use of immune checkpoint inhibitors (ICIs) for the treatment of various malignancies, however, more cases are likely to be diagnosed in the future. We present a patient who received her first cycle of pembrolizumab therapy 3 weeks prior to presentation with complaints of intense myalgias, diffuse muscle weakness and ptosis. Investigative workup revealed myocarditis, myositis and myasthenia gravis. Treatment with high-dose steroids plus plasma exchange drastically improved her symptoms. This case demonstrates the presenting symptoms, diagnostic findings, critical complications and management strategies of Triple M Overlap Syndrome.

A series of 2-benzyl-4-substituted-2-azabicyclo[3.2.1]octanes, derived from the E-F ring of aconitine scaffold, were designed as potential anticancer agents. Utilizing two key reactions, asymmetric aza-Diels-Alder addition and SN2 type ring expansion, to construct the core bicyclic skeleton, forty-one target compounds (11a-v and 13a-s) were successfully synthesized. Most of the target compounds exhibited considerable antiproliferative effects against four cancer cell lines (A549, HT-29, HepG2 and MDA-MB 231) with low IC50 values. Among them, compound 13l showed the most potent antiproliferative activity against HT-29 colorectal cancer (CRC) cells, and displayed significant heat shock protein 90 (Hsp90) inhibitory activity. Molecular modeling studies supported the experimental results and the key interactions were identified. Further investigation indicated that 13l could effectively suppress the proliferation and migration of HT-29 cells, along with inducing cell cycle arrest and mild apoptosis via down-regulation of CDK12, CDK13 and Bcl-2 protein expressions, and up-regulation of Bax. Mechanistic studies revealed that 13l could inhibit Hsp90 to destabilize EGFR and suppress the activation of the EGFR-Akt signaling pathway to reduce proliferation of HT-29 cells. Consistent with in vitro results, 13l significantly repressed tumor growth in an HT-29 xenograft mouse model without causing evident cytotoxicity. Therefore, 13l could be considered as a novel and potentially effective candidate for the future treatment of CRC.

Pembrolizumab has revolutionised the treatment of melanoma. Immune checkpoint inhibitors (ICI) are well tolerated in trials, but the real-world incidence of toxicities and their management are not well described. We investigated the incidence and management of toxicities in New Zealand.

ATM plays a critical role in maintaining genomic stability and represents a promising antitumor target. Building upon previously reported ATR/ATM dual-target inhibitor, we rationally designed a series of 1H-pyrrolo[2,3-b]pyridine derivatives as highly selective ATM inhibitors. Through systematic structural optimization, compound 25a was identified as the lead candidate, exhibiting excellent kinase selectivity (>700-fold over PIKK family members) in vitro. Notably, 25a demonstrated excellent drug-like properties with an oral bioavailability of 147.6% in mice. Mechanistically, the synergistic antitumor efficacy of 25a combined with irinotecan relied on inhibition ATM pathway. In HCT116 and SW620 xenograft models, 25a combined with irinotecan demonstrated a synergistic antitumor efficacy with TGI of 79.3% and 95.4%, respectively. These findings position 25a as a novel chemosensitizer candidate for combination therapy in solid tumors.