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In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a "fatty alcoholization" strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC 12 , AC 16 , AC 20 , AC 24) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC 12 to AC 20), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC 24 , the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC 20 PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies. PTX-AC 20 with modest chain length of modification modules stood out for the superior self-assemble ability, modest redox-sensitivity, and favorable tolerance. [Display omitted] • The "fatty alcoholization" strategy was endowed PTX with self-assembly ability. • The role of modification modules in PTX prodrug nanoassemblies was clarified. • The optimal chain length was modest in constructing PTX prodrug nanoassemblies. • PTX-AC 20 PNs with proper chain length outperformed in efficacy and tolerance. [ABSTRACT FROM AUTHOR]

• The aqueous extract of Annona muricata leaves contains high levels of flavonoids and polyphenols. • A remarkable reduction in tumor size was discovered using a mouse model of mastocytoma in Dba/2 mice. • The aqueous extract of Annona muricata has anti-tumor properties. • The in vivo study demonstrated a correlation between the reduction of oxidative stress and the anti-tumor properties following the treatment of Dba/2 mice with the aqueous extract of Annona muricata orally. The medicinal plant Annona muricata of the Annonaceae family, also called Graviola, native to the Andean highlands of Peru and Ecuador but also widespread in Chile, California, Florida, southern Africa and various Mediterranean countries, has various beneficial properties for health and has been the subject of several studies for its anti-tumor activity. In this work, a phytochemical analysis of the aqueous extract of Annona muricata by using HPLC technique to evaluate the content of total polyphenols, flavonoids and tannins, was performed. In addition, for the first time, an evaluation of the effect of the aqueous extract on a Dba/2 transgenic mouse model carrying a P815 tumor, was established. Following the administration of oral doses of 250 and 500 mg/kg for 30 days, a decrease in the volume and weight of the tumors was detected. Furthermore, a correlation between the reduction of oxidative stress and the anticancer properties of Annona muricata, was demonstrated. In conclusion , the aqueous extract of Annona muricata may provide a new therapeutic approach to manage unwanted growth of mastocytoma (P815 tumor) by targeting oxidative stress. [ABSTRACT FROM AUTHOR]

Animal venoms are a rich and complex source of components, including peptides (such as neurotoxins, anionic peptides and hypotensins), lipids, proteins (such as proteases, hyaluronidases and phospholipases) and inorganic compounds, which affect all biological systems of the envenoming victim. Their action may result in a wide range of clinical manifestations, including tachy/bradycardia, hyper/hypotension, disorders in blood coagulation, pain, edema, inflammation, fever, muscle paralysis, coma and even death. Scorpions are one of the most studied venomous animals in the world and interesting bioactive molecules have been isolated and identified from their venoms over the years. Tityus spp. are among the scorpions with high number of accidents reported in the Americas, especially in Brazil. Their venoms have demonstrated interesting results in the search for novel agents with antimicrobial, anti-viral, anti-parasitic, hypotensive, immunomodulation, anti-insect, antitumor and/or antinociceptive activities. Furthermore, other recent activities still under investigation include drug delivery action, design of anti-epileptic drugs, investigation of sodium channel function, treatment of erectile disfunction and priapism, improvement of scorpion antivenom and chelating molecules activity. In this scenario, this paper focuses on reviewing advances on Tityus venom components mainly through the modern omics technologies as well as addressing potential therapeutic agents from their venoms and highlighting this abundant source of pharmacologically active molecules with biotechnological application. [Display omitted] • Tityus venoms are still underexploited sources of pharmacological agents. • Only few Tityus venom sequences (of ∼3000 available at databases) have been studied in depth. • T. serrulatus venom is the most studied venom among the Tityus venoms. • Many Tityus toxins are versatile toxins presenting a broad spectrum potential. • Some Tityus venom components whose function is still unknown include the PAPE and anionic peptides. [ABSTRACT FROM AUTHOR]

Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines. In the current project, the first total synthesis of (±)-MPE was achieved in seven steps and 5.6% overall yield. Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells, with the levoisomer exerting slightly better potency. The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model. Notably, MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage. Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling. In conclusion, our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies. The first total synthesis of (±)-mornaphthoate E, identified as tubulin inhibitor, was achieved. The in vitro and in vivo antitumor effects were evaluated for pure enantiomers and racemate, respectively. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly (ADP-ribose) polymerase 1 (PARP1). Among these derivatives, compound 5d emerged as the most effective chrysin-based inhibitor of PARP1, with an IC 50 value of 108 nmol·L−1. This compound significantly inhibited the proliferation and migration of breast cancer cell lines HCC-1937 and MDA-MB-436 by inducing DNA damage. Furthermore, 5d induced apoptosis and caused an extended G 1 /S-phase in these cell lines. Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1. In vivo , in a xenograft model, 5d effectively reduced tumor growth by downregulating PARP1 expression. Overall, compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer. [ABSTRACT FROM AUTHOR]

• This review summarizes the Mg alloys developed for antitumor applications, which has dual function of antitumor and tissue regeneration. • The antitumor effects of Mg alloys are mainly due to their degradation products. • The mechanisms of Mg alloys on tumor inhibition are discussed. Cancer is a major threat to human life worldwide. Traditional cancer treatments, such as chemotherapy and surgery, have major limitations and can cause irreversible damage to normal tissues while killing the cancer cells. Magnesium (Mg) alloys are widely reported novel potential biomedical materials with acceptable mechanical properties and good osteogenic and angiogenic properties. In this review, we summarize the Mg alloys for antitumor applications, including pure Mg and Mg alloys (Mg-Ag, Mg-Gd, Mg-Li-Zn, Mg-Ca-Sr-Zn, et al.) fabricated by casting and extruding, selective laser melting methods. Mg alloys can exhibit antitumor effect on bone tumor, breast cancer, and liver tumor, etal. What's more, after tumor tissue is eliminated, Mg alloys prevent tumor recurrence, fill tissue defects and promote tissue regeneration. The antitumor effects of Mg alloys are mainly due to their degradation products. Overall, Mg alloys show great potential in tumor treatments due to the dual function of antitumor and tissue regeneration. [ABSTRACT FROM AUTHOR]

NO gas therapy is a supplementary approach for tumor treatment due to the advantages of minimal invasion, little drug resistance, low side effect and amplified efficacy. l -Arginine (L-Arg), a natural NO source with good biocompatibility, can release NO under the stimulation of H 2 O 2 in tumor microenvironment. However, the conventional l -Arg delivery systems via noncovalent loading usually lead to inevitable premature leakage of nano-cargos during blood circulation. In this work, an efficient l -Arg self-delivery supramolecular nanodrug (SDSND) for tumor treatment is demonstrated by combining Mannich reaction and π-π stacking. l -Arg links to (-)-epigallocatechin gallate (EGCG) with the assistance of formaldehyde through Mannich reaction, and then assembles into nanometer-sized particles via π-π stacking. The guanidine group of l -Arg and the phenolic hydroxyl groups of EGCG are preserved in the SDSNDs, which allows for accomplishing gas therapy by provoking tumor cell apoptosis and combining with EGCG to amplify apoptosis, respectively. In addition, the SDSNDs exhibit high biocompatibility and avoid the premature leakage of l -Arg in blood circulation, providing an alternative l -Arg delivery system for NO gas therapy. NO gas therapy has attracted emerging interest in tumor treatment. However, the controlled NO release and the avoidance of premature leakage of NO donors remain challenging. In this work, L-Arginine (L-Arg) self-delivery supramolecular nanodrug for efficient tumor therapy is demonstrated through the Mannich reaction of L-Arg, (-)-epigallocatechin gallate (EGCG) and formaldehyde. Stimulated by tumor microenvironment, the guanidine groups of L-Arg allow for accomplishing NO release and thus provoking tumor cell apoptosis. The nanodrug also avoids the premature leakage of L-Arg in blood circulation. Moreover, the preserved phenolic hydroxyl groups of EGCG combine with L-Arg to amplify apoptosis. The nanodrug exhibits high biocompatibility and good therapeutic effect, providing an alternative L-Arg delivery system for NO gas therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

The utilization of light for therapeutic interventions, also known as phototherapy, has been extensively employed in the treatment of a wide range of illnesses, including cancer. Despite the benefits of its non-invasive nature, phototherapy still faces challenges pertaining to the delivery of phototherapeutic agents, phototoxicity, and light delivery. The incorporation of nanomaterials and bacteria in phototherapy has emerged as a promising approach that leverages the unique properties of each component. The resulting nano-bacteria biohybrids exhibit enhanced therapeutic efficacy when compared to either component individually. In this review, we summarize and discuss the various strategies for assembling nano-bacteria biohybrids and their applications in phototherapy. We provide a comprehensive overview of the properties and functionalities of nanomaterials and cells in the biohybrids. Notably, we highlight the roles of bacteria beyond their function as drug vehicles, particularly their capacity to produce bioactive molecules. Despite being in its early stage, the integration of photoelectric nanomaterials and genetically engineered bacteria holds promise as an effective biosystem for antitumor phototherapy. The utilization of nano-bacteria biohybrids in phototherapy is a promising avenue for future investigation, with the potential to enhance treatment outcomes for cancer patients. [Display omitted] • Nano-bacteria biohybrids improve targeted delivery of drugs. • Nano-bacteria biohybrids stimulate immune responses to enhance antitumor performance. • Nano-bacteria biohybrids show promise in antitumor phototherapies. • Synthetic biology expands possibilities of nano-bacteria biohybrids. [ABSTRACT FROM AUTHOR]

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis. [ABSTRACT FROM AUTHOR]

The leaves of Zizyphus spina-christi (L.) Willd contain several compounds exhibiting different pharmacologic activities. However, studies on the cytotoxic activity of these compounds are limited. We aimed to investigate and isolate cytotoxic compounds with selective antitumor effects from the leaves of Z. spina-christi using bioassay-guided fractionation of methanol extract. Powdered, dried leaves were subjected to methanol extraction and fractionated using n -hexane, chloroform, ethyl acetate, and n -butanol. Fractions with positive cytotoxicity against HeLa and THP-1 cell lines were further fractionated and eluted using various concentrations of organic solvents. Active compounds were isolated using different chromatographic methods and their chemical structures were determined using extensive spectroscopic methods, such as 1D NMR (1H NMR, 13C NMR, and DEPT), 2D NMR (COSY, HMBC, and HMQC), HRFAB-MS, and IR. Furthermore, the cytotoxic effects of the isolated compounds were evaluated against 62 tumor cell lines (including HeLa and THP-1) in addition to normal bone marrow cells. The chloroform and aqueous methanol fractions of the leaves showed cytotoxic activity. Two compounds were successfully isolated and named "sidrin" (13-β-hydroxy-lup-20(30)-ene-2,3-β-epoxy-28-carboxylate) and "sidroside" (3- O -β-D-glucopyranosyl-(1–3)-α-L-arabinopyranosyl-jujubogenin-20- O -α-L-rhamnopyranoside). Sidrin exhibited cytotoxic activity against the human leukemia (Hl-60, RPMI-8226), lung cancer (A549, EKVX), breast cancer (BT-549, MDA-MB-231/ATCC), colon cancer (KM12), melanoma (M14, SK-MEL-5), and central nervous system (CNS) cancer (SF-295) cell lines, and selectivity was observed against the Hl-60, EKVX, BT-549, KM12, and SF-295 cell lines. In addition, sidrin was more active than sidroside and doxorubicin against the Hl-60 and EKVX cell lines. In contrast, sidrin had a similar effect to doxorubicin against the BT-549 and renal cancer (UO-31) cell lines. Sidroside was more selective against the leukemia (CCRF-CEM, MOLT-4), lung cancer (HOP-92, NCI-H322M), breast cancer (MDA-MB-468), melanoma (LOX IMVI), CNS cancer (SNB-19), ovarian cancer (OVCAR-8), renal cancer (UO-31, RXF 393), and prostate cancer (PC-3) cell lines. Both compounds exhibited similar activity against the breast cancer (MDA-MB-231, T-47D), colon cancer (HCC-2998, HCT-116), ovarian cancer (OVCAR-3), renal cancer (UO-31, 786–0, and SN 12C) cell lines. Normal bone marrow cells were unaffected at the same concentrations of sidrin and sidroside applied to tumor cells. These results suggest tumor-selective cytotoxicity of sidrin and sidroside. [ABSTRACT FROM AUTHOR]

CRISPR-Cas9 is a central focus of the emerging field of gene editing and photodynamic therapy (PDT) is a clinical-stage ablation modality combining photosensitizers with light irradiation. But metal coordination biomaterials for the applications of both have rarely been investigated. Herein, Chlorin-e6 (Ce6) Manganese (Mn) coordination micelles loaded with Cas9, termed Ce6-Mn-Cas9, were developed for augmented combination anti-cancer treatment. Manganese played multiple roles to facilitate Cas9 and single guide RNA (sgRNA) ribonucleoprotein (RNP) delivery, Fenton-like effect, and enhanced endonuclease activity of RNP. Histidine (His)-tagged RNP could be coordinated to Ce6 encapsulated in Pluronic F127 (F127) micelles by simple admixture. Triggered by ATP and endolysosomal acidic pH, Ce6-Mn-Cas9 released Cas9 without altering protein structure or function. Dual guide RNAs were designed to target the antioxidant regulator MTH1 and the DNA repair protein APE1, resulting in increased oxygen and enhanced PDT effect. In a murine tumor model, Ce6-Mn-Cas9 inhibited tumor growth with the combination therapy of PDT and gene editing. Taken together, Ce6-Mn-Cas9 represents a new biomaterial with a high degree of versatility to enable photo- and gene-therapy approaches. [Display omitted] [ABSTRACT FROM AUTHOR]

The combination of photothermal treatment and chemodynamic therapy has attracted extensive attention for improving therapeutic effects and compensating the insufficiency of monotherapy. In this work, a copper-metal organic framework (Cu-BTC) was used to augment the photothermal effect of polydopamine (PDA) and endow it with a chemodynamic ability by constructing a Cu-BTC@PDA nanocomposite. Density functional theory calculations revealed that the plasmonic vibrations formed by the d-d transition of Cu at the Fermi level in Cu-BTC@PDA could enhance the photothermal performance of PDA. In addition, more Cu2+ released from Cu-BTC@PDA in the acidic microenvironment of the tumor was then reduced to Cu+ by glutathione (GSH) and further catalyzed H 2 O 2 to generate more toxic hydroxyl radical (•OH), which synergized with photothermal treatment for melanoma therapy. Furthermore, Cu-BTC@PDA could quickly and effectively kill bacteria under the action of PTT, and the sustained release of Cu ions could contribute to the long-term and stable bacteriostatic ability of the material. This sustained release of Cu ions could also promote the cell migration and angiogenesis, and upregulate the expression of COL -, TGF -, and VEGF -related genes to accelerate wound healing. This multifunctional nanomaterial has potential application in the treatment of melanoma and repair of wounds. We constructed a multifunctional nanoplatform (Cu-BTC@PDA) by two steps. This nanoplatform can not only perform cascade catalysis in the tumor microenvironment to generate more toxic hydroxyl radical (•OH), but also synergize with photothermal treatment for melanoma therapy. Additionally, Cu-BTC@PDA possesses enhanced photothermal performance through the plasmonic vibrations formed by the d-d transition of Cu at the Fermi level in Cu-BTC@PDA, which is revealed by DFT calculations. And Cu-BTC@PDA shows good antitumor, antibacterial, and wound healing properties in vivo and in vitro. Such a multifunctional nanomaterial has potential application in the treatment of melanoma and repair of wounds. [Display omitted] [ABSTRACT FROM AUTHOR]

Photothermal therapy is a novel strategy for cancer treatment, which can kill tumor cells by converting light energy into heat energy through irradiating photothermal conversion materials with laser. As a common photothermal agent, gold nanorods (GNRs) have characteristics of high conversion efficiency and long circulation time in vivo. However, improving stability and reducing toxicity of GNRs remain a significant challenge. In this research, a simple and novel strategy for the synthesis of modified GNRs was proposed. The polysaccharide CL90 was obtained from lemon, which was modified to afford thiolated lemon polysaccharide (SH-CL90). SH-CL90 was used to prepare stable GNRs and give the composite GNRs-SH-CL90, which was found to have good stability in PBS solution and possess high photothermal conversion effects and photothermal stability. The biological experiments revealed that GNRs-SH-CL90 inhibited tumor cell proliferation under near-infrared light irradiation and could induce apoptosis significantly. Furthermore, in vivo experiments supported that GNRs-SH-CL90 could inhibit the proliferation and migration of tumor cells. All the experiments demonstrated that GNRs-SH-CL90 might be promising in the field of cancer treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Novel 2-amino-4-(aminomethyl)thiazole derivatives were designed and synthesized by a facile method including the Hantzsch construction of thiazole core followed by amidation and nucleophilic substitution steps. Bioassay results showed that 4-(tert -butyl)- N -[4-(piperazin-1-ylmethyl)thiazol-2-yl]-benzamide and 4-(tert -butyl)- N -{4-[(4-piperidinopiperidin-1-yl)methyl]thiazol-2-yl}benzamide possessed similar activities compared with 5-fluorouracil. The 4-piperidino-piperidin-1-yl-containing derivative also suppressed proliferation of cultured tumor cells by inducing apoptosis. [ABSTRACT FROM AUTHOR]

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC 50 value of 0.68 μM, outperforming the lead compound PAB (IC 50 = 5.44 μM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis. [Display omitted] • 37 PAB derivatives tested on VEGF inhibition in hypoxic SiHa cells. • Compound M2 was the most potent inhibitor with an IC 50 value of 0.68 μM. • M2 inhibits HIF-1α accumulation/translocation, downregulating VEGF expression. • M2 modulates PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells. • In vivo studies show low toxicity and effective tumor growth suppression by M2. [ABSTRACT FROM AUTHOR]

Pyridazinone derivatives have been extensively used as anticancer agents. IMB5036 is a structure specific pyridazinone compound with potential antitumor activity via targeting KSRP protein which controls gene expression at multiple levels. In this study, fifteen IMB5036 analogues were synthesized and preliminary structure-activity relationships were explored. Among them, compounds 8 and 10 exhibited remarkably anti-proliferation of various cancer cells and a good cancer cell selectivity (against human fetal hepatocyte L02 cells). More detailed investigation was included that both 8 and 10 inhibited colony formation and migration in concentration-dependent mode against MCF-7 cells. Additionally, 8 and 10 induced apoptosis and cell cycle arrest, decreased mitochondrial membrane potential, damaged DNA, and increased reactive oxygen species. Moreover, 8 displayed a potent antitumor efficacy (TGI = 74.2 %, at a dose of 30 mg/kg) in MCF-7 xenograft model by i.p. injection. Further, we synthesized a biotinylated probe 16 for identifying the detail domain of KSRP. Through pull down assay and molecular docking study, we validated that the KH23 domain functioned as the binding pocket for the compounds. Thus, compound 8 was identified as a novel targeting KSRP pyridazinone-based compound and exhibited excellent antitumor activity both in vitro and in vivo. [Display omitted] • Fifteen IMB5036 derivatives were synthesized and investigated as antitumor agents. • Compounds 8 and 10 displayed potent cytotoxicity in multiple cancer cells. • Compound 8 showed binding affinity to KSRP, especially binding to KH23 domain. • Compound 8 had potent in vivo antitumor effects. [ABSTRACT FROM AUTHOR]

• We discovered that Mn2+ treatment led to a significant increase in KLRG1+macrophages (Mφ) in tumor tissues, and most of these cells exhibited an M1 phenotype. • We found that knocking down KLRG1 expression in macrophages not only impaired their ability to induce downstream anti-tumor immunity of adaptive immune cells, but also impaired their direct cytotoxicity against tumor cells. • Our study expands the understanding of the anti-tumor mechanism of Mn2+ and demonstrates, for the first time, that Mn2+ can regulate the function of KLRG1+Mφ to participate in anti-tumor activities. Manganese (Mn) play a crucial role in various biological processes in the body. Studies have primarily focused on their ability to enhance immune cell function and activation against tumors, particularly in dendritic cells (DCs), macrophages, and T cells. Tumor-associated macrophages (TAMs) are often the most abundant immune cell population present in the tumor microenvironment (TME). Thus, it would be valuable to investigate the mechanism by which Mn2+ regulates TAMs' involvement in anti-tumor immunity, as it be crucial for advancing our understanding of cancer biology and developing new treatments for cancer. Here, in the present study we discovered that Mn2+ treatment led to a significant increase in KLRG1+ macrophages (KLRG1+ Mφ) in tumor tissues, and most of these cells exhibited an M1 phenotype. Knocking down KLRG1 in macrophages not only impaired their ability to induce downstream anti-tumor immunity of adaptive immune cells, but also impaired their direct cytotoxicity against tumor cells. Moreover, the changes in the polarization phenotype of KLRG1+ macrophages further lead to T cell proliferation and the polarization of CD4+ T cells towards a Th1 phenotype, thereby establishing a foundation for the antitumor immune response. Our study expands the understanding of the anti-tumor mechanism of Mn2+ and demonstrates, for the first time, that Mn2+ can regulate the function of KLRG1+ Mφ to participate in anti-tumor activities. These findings suggest that KLRG1 may represent a promising target for developing new tumor therapy. [ABSTRACT FROM AUTHOR]

Mitochondria have been recognized as a significant target for cancer therapy due to their vital role in many basic cell functions. In recent years, the development of mitochondrial targeted anti-tumor drugs has become important research directions. Herein, We report three new targeted preparations (FEQ-TPP, FEQ-BDP, and FEQ-TEA), which were synthesized by conjugating triphenylphosphine (TPP), Bodipy-pyridine salt (BDP) and triethylamine salt (TEA) with phenoxazine (FEQ). It was observed that greater delocalization range of TPP cationic carriers can enhance the recognition and accumulation efficiency of FEQ-TPP in tumor cell mitochondria. As a result, FEQ-TPP exhibits excellent mitochondrial targeting and significant anti-tumor selectivity; FEQ-BDP can show the ability of real-time fluorescence imaging. This research provides valuable insights for the screening of mitochondrial targeting vectors and the subsequent exploration and development of targeted anti-tumor medications, particularly those based on phenoxazine and its derivatives. [Display omitted] • FEQ-TPP demonstrated remarkable antitumor selectivity. • FEQ-BDP showed real-time fluorescence imaging and excellent mitochondrial targeting ability. • Different lipophilic cations have different effects. [ABSTRACT FROM AUTHOR]

Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products. [Display omitted] • Compound 18 showed excellent activity against both STAT3 and HDAC. • Compound 18 induces autophagy and apoptosis. • Compound 18 self-assembled in water to form nanoparticles (18 NPs). • The 18 NPs exhibited better retention and accumulation properties than free 18. [ABSTRACT FROM AUTHOR]

Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C–R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C–R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C–R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities. [Display omitted] • Designed and synthesized 26 novel human leukemia cells and lymphocyte cells targeted penetrating peptides. • These modified peptides had good permeability and targeting properties to K562 cells, KU812 cells and CCRF-CEM cells. • C9C-f(3Bta) or Cyclo-C9C–R had potent IMA-PROTAC co-application effects against K562 cells at low concentrations. • The combination of C9C-f(3Bta) or Cyclo-C9C–R with IMA-PROTAC can improve the degradation of Bcr-Abl protein. [ABSTRACT FROM AUTHOR]

Cancer remains one of the greatest global health concerns. This is especially true for gynecological cancers, which include cervical, ovarian, and endometrial cancers, and breast cancer. Natural products used for cancer treatment offer some unique advantages. Triptolide (TPL) is a biologically active terpenoid extracted from Tripterygium wilfordii , which exhibits anti-inflammatory, immunosuppressive, antitumor, and other pharmacological activities. However, clinical applications of TPL are restricted because of poor water solubility and severe cytotoxicity; to overcome these limitations, various TPL derivatives and drug delivery systems, especially nanocarriers, have been used. Furthermore, various preclinical and clinical studies have demonstrated that TPL and its derivatives exhibit excellent antitumor effects by targeting proteins involved in multiple signaling pathways. Here, we review the progress regarding novel drug delivery systems, antitumor activities, and molecular mechanisms of action of TPL and its derivatives against gynecological and breast cancers. TPL and its derivatives inhibit tumor growth, suppress tumor metastasis, and enhance the drug sensitization of resistant cancers. In addition, TPL and its derivatives exert synergistic antitumor effects against gynecological and breast cancers when combined with existing antitumor drugs, such as carboplatin, cisplatin, and PI3K inhibitors. Moreover, we highlight the clinical potential of TPL analogs against cancer from bench to bedside and their prospects for future applications in gynecologic and breast cancers. [Display omitted] • TPL and its derivatives exhibit excellent antitumor effects. • TPL and its derivatives can be a promising candidate for combination therapy. • TPL analogs is being used in clinical trials for various cancers. [ABSTRACT FROM AUTHOR]

[Display omitted] • 32 lupeol derivatives were designed, synthesized and evaluated for their cytotoxic activity. • Compound 6c and 14f exhibited potent cytotoxic activity against A549 cell line. • Compound 14f induced A549 cells apoptosis via the mitochondria related pathway. • Compound 14f inhibited tumor growth in vivo zebrafish xenograft tumor A549 cell model. Lupeol is a natural pentacyclic triterpenoid with a wide range of biological activities. To improve the water solubility and targeting of lupeol, in the following study, we synthesized 27 lupeol derivatives in the first series by introducing lipophilic cations with lupeol as the lead compound. Through the screening of different cancer cells, we found that some of the derivatives showed better activity than cisplatin against human non-small cell lung cancer A549 cells, among which compound 6c was found to have an IC 50 value of 1.83 μM and a selectivity index of 21.02 (IC 50 MRC-5/IC 50 A549) against A549 cells. To further improve the antiproliferative activity of the compounds, we replaced the ester linkage of the linker with a carbamate linkage and synthesized a second series of five lupeol derivatives which were screened for activity, among which compound 14f was found to have an IC 50 value of 1.36 μM and a selectivity index of 15.60 (IC 50 MRC-5/IC 50 A549) against A549 cells. We further evaluated the bioactivity of compounds 6c and 14f and found that both compounds induced apoptosis in A549 cells, promoted an increase in intracellular reactive oxygen species and decrease in mitochondrial membrane potential, and inhibited the cell cycle in the S phase. Of the compounds, compound 14f showed stronger bioactivity than compound 6c. We then selected compound 14f for molecular-level Western blot evaluation and in vivo evaluation in the zebrafish xenograft A549 tumor cell model. Compound 14f was found to significantly downregulate Bcl-2 protein expression and upregulate Bax, Cyt C, cleaved caspase-9, and cleaved caspase-3 protein expression, and 14f was found to be able to inhibit the proliferation of A549 cells in the zebrafish xenograft model. The above results suggest that compound 14f has great potential in the development of antitumor drugs targeting mitochondria. [ABSTRACT FROM AUTHOR]

An ideal tumor treatment strategy involves therapeutic approaches that can enhance the immunogenicity of the tumor microenvironment while simultaneously eliminating the primary tumor. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been reported to exhibit potent type I and type II photodynamic therapeutic effects against triple-negative breast cancer (MDA-MB-231). This photosensitizer induces pyroptotic cell death mediated by gasdermin E (GSDME) through photodynamic means and enhances tumor immunotherapy. Mechanistic studies have revealed that complex Ir3 induces characteristics of damage-related molecular patterns (DAMPs) in MDA-MB-231 breast cancer cells under light conditions. These include cell-surface calreticulin (CRT) eversion, extracellular high mobility group box 1 (HMGB1) and ATP release, accompanied by ER stress and increased reactive oxygen species (ROS). Consequently, complex Ir3 promotes dendritic cell maturation and antigen presentation under light conditions, fully activates T cell-dependent immune response in vivo , and ultimately eliminates distant tumors while destroying primary tumors. In conclusion, immune regulation and targeted intervention mediated by metal complexes represent a new and promising approach to tumor therapy. This provides an effective strategy for the development of combined targeted therapy and immunotherapy. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been demonstrated to exhibit potent type I and type II photodynamic therapeutic effects. Ir3 can induce pyroptosis to enhance tumor immunogenicity, thus ultimately eliminating the distant tumor while destroying the primary tumor in vivo. [Display omitted] • A cholic acid (CA)-functionalized iridium(III) photosensitizer was designed. • It accumulates in ER and precisely disrupts ER with type I and II ROS generation. • The ER stress induced pyroptosis eminently amplified immunogenic cell death. • PDT evokes systemic antitumor immunity, eliminating primary and distant tumors. [ABSTRACT FROM AUTHOR]

Mitophagy is an important target for antitumor drugs development. A series of ciclopirox (CPX) platinum(IV) hybrids targeting PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitophagy were designed and prepared as antitumor agents. The dual CPX platinum(IV) complex with cisplatin core was screened out as a candidate, which displayed promising antitumor activities both in vitro and in vivo. Mechanistically, it caused serious DNA damage in tumor cells. Then, remarkable mitochondrial damage was induced accompanied by the mitochondrial membrane depolarization and reactive oxygen species generation, which further promoted apoptosis through the Bcl-2/Bax/Caspase3 pathway. Furthermore, mitophagy was ignited via the PINK1/Parkin/P62/LC3 axis, and exhibited positive influence on promoting the apoptosis of tumor cells. The antitumor immunity was boosted by the block of immune check point programmed cell death ligand-1 (PD-L1), which further increased the density of T cells in tumors. Subsequently, the metastasis of tumor cells was inhibited by inhibiting angiogenesis in tumors. Ciclopirox platinum(IV) hybrids were designed and prepared as antitumor agents, which activated by damaging mitochondria, provoking prodeath mitophagy, and activating immune responses in tumor tissues, besides inducing DNA damage. A candidate complex was screened out possessing potent antitumor efficacy in vivo but causing rather low toxicity. [Display omitted] • Ciclopirox platinum(IV) complexes were developed as new potent antitumor agents. • Effective in igniting mitophagy and boosting T cell immunity. • Inhibit tumor metastasis by inhibiting angiogenesis. [ABSTRACT FROM AUTHOR]

Complexes [Cu(PI) 2 (H 2 O)](NO 3) 2 (1), [Cu(PBI) 2 (NO 3)]NO 3 (2), [Cu(TBI) 2 (NO 3)]NO 3 (3), [Cu(BBIP) 2 ](ClO 4) 2 (4) and [Cu(BBIP)(CH 3 OH)(ClO 4) 2 ] (5) were synthesized from the reactions of Cu(II) salts with 2-(2′-pyridyl)imidazole (PI), (2-(2′-pyridyl)benzimidazole (PBI), 2-(4′-thiazolyl)-benzimidazole (TBI), 2,6-bis(benzimidazol-2-yl)-pyridine (BBIP), respectively. Their compositions and crystal structures were determined. Their in-vitro antitumor activities were screened on four cancer cell lines and one normal cell line (HL-7702) using cisplatin as the positive control. Complexes 2 and 4 show higher cytotoxicity than the other three complexes. The cytotoxicity of complex 2 are comparable to those for cisplatin, and the cytotoxicity for 4 are much higher than those for cisplatin. From a viewpoint of antitumor, 2 might be a nice choice on the tumor cell line of T24 because its IC50 values on T24 and HL-7702 are 15.03 ± 1.10 and 21.34 ± 0.35, respectively. Thus, a mechanistic study for complexes 2 and 4 on T24 cells was conducted. It revealed that they can reduce mitochondrial membrane potential and increase mitochondrial membrane permeability, resulting in increased intracellular ROS levels, Ca2+ inward flow, dysfunctional mitochondria and the eventual cell apoptosis. In conclusion, they can induce cell apoptosis through mitochondrial dysfunction. These findings could be useful in the development of new antitumor agents. We report here five Cu(II) complexes bearing imidazole derivative ligands with different ligand skeletons, some of which present cytotoxicity comparable to cisplatin or even higher than cisplatin. [Display omitted] • Complexes with different ligand skeletons and structures show different cytotoxicity; • Some complexes present cytotoxicity comparable to or even higher than cisplatin; • Cell apoptosis through mitochondrial pathway. [ABSTRACT FROM AUTHOR]

Alginate is a natural polysaccharide obtained from brown seaweeds and having advantageous health usefulness, was employed extensively in nutraceutical sectors and the pharmaceutical industry. This research was devoted for optimization of alginate extraction from different brown seaweeds. A Box-Behnken Design (BBD) was used for the optimization of alginate extraction from Padina pavonica by analyzing the influence of temperature (30, 40, and 50 °C), time (60, 120, and 180 min), and alkaline concentration (1 %, 2 %, and 3 %) on extraction yield and uronic acid content. The optimal conditions recorded to maximize the alginate yield and its uronic content were an alkali concentration of 2.5 % and a temperature of 39.95 °C for 102.5 min. The optimized parameters achieved from BBD were used to compare alginate extraction from P. pavonica, Sargassum cinereum, Turbinaria turbinata, and Dictyota dichotoma. FTIR, 1H NMR, and HPLC were used to characterize the extracted alginate. The bioactivity of alginate against free radicals, breast cancer cells (MCF-7), some pathogenic microbes, and SARS-CoV-2 viruses was tested. Under the optimized conditions, alginate was extracted from P. pavonica at a rate of 21.13 ± 2.47 % DW, S. cinereum at 24.08 ± 0.33 % DW g/L, T. turbinata at 17.47 ± 0.26 % DW, and D. dichotoma at a rate of 19.57 ± 3.60 % DW. The alginate extracted from D. dichotoma showed the highest antioxidant, anticancer, and antiviral activity. [ABSTRACT FROM AUTHOR]

• Two thiosemicarbazone-based Cu complexes with proapoptotic activity were synthesized. • Complex 1 bound to DNA via an intercalation mode and arrested cell cycle in S phase. • Complex 1 enhanced ROS generation, caused mitochondria dysfunction and ATP depletion. The copper ion and thiosemicarbazone group are well known for their biological activity, endowing the thiosemicarbazone copper complexes with medicinal perspectives. In this work, two copper complexes [Cu(qcpt)(PPh 3) 2 Br]·2CH 3 CN (1) and [Cu 2 (qcapt)(Ac) 2 (CH 3 O)] (2) derived from the bioactive quinoline-thiosemicarbazone conjugate (qcpt = quinoline-2- carboxaldehyde-4-pyridine-3-thiosemicarbazone; qcapt = quinoline-2-carboxaldehyde acid-4- pyridine-3-thiosemicarbazone) were rationally synthesized and characterized by single crystal X-ray diffraction, Infrared (IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and etc. In vitro antitumor studies suggested that complexes 1 and 2 showed effective anti-proliferative activity against malignant tumor cells, especially for complex 1 that exhibited the most sensitive against SMMC7721 cells (human liver carcinoma cell lines). Further, mechanistic studies showed that complex 1 could readily enter the cells, block the cell cycle, cause mitochondrial dysfunction and ATP depletion, enhance the levels of intracellular reactive oxygen species (ROS), and eventually trigger cell death via apoptosis. Additionally, complex 1 bound to CT-DNA via an intercalation mode as evidenced by spectroscopic experiments, molecular docking study and cleaved pBR322 DNA efficiently in the presence of H 2 O 2. Copper complex 1 demonstrated most sensitive against SMMC7721 cells. The mechanistic studies elucidated that complex 1 could enter the cells, arrest the cell cycle, elicit ROS overproduction and cause mitochondrial dysfunction accompanied with ATP depletion. Eventually, complex 1 triggered apoptotic tumor cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Anthracyclines belong to a class of anti-tumor antibiotics, and their severe cardiotoxicity significantly limits their clinical use. Exosomes play key roles in intercellular communication, characterized by high biocompatibility and specific tissue and organ homing effects. In this study, doxorubicin, an anthracycline anticancer drug widely used in clinical chemotherapy, was selected as a model drug. To address the significant cardiotoxicity associated with doxorubicin, tumor exosomes are utilized as drug carriers. The homing effect of autologous exosomes enhances drug uptake by tumor cells and reduces cardiotoxicity. To enhance the stability of exosomes, improve therapeutic effectiveness, and reduce toxic side effects, chitosan was utilized to modify the surface of exosomes. Chitosan has a specific anti-tumor effect because it can target the CD44 receptor of tumor stem cells and interact with tumor cells through charge adsorption. Through in vitro cell experiments, in vivo pharmacokinetic experiments, and an in situ ectopic nude mouse tumor model, the study demonstrated that chitosan-modified tumor exosomes significantly alleviated the severe cardiotoxicity of doxorubicin, while also showing remarkable anti-tumor efficacy. This study introduces a novel approach to reduce the adverse side effects of anthracycline chemotherapeutic drugs and presents a highly promising nanocarrier delivery system. [Display omitted] [ABSTRACT FROM AUTHOR]

Natural small molecule catechins (CC) show significant promise in preventing and treating cervical cancer due to their remarkable anti-HPV, antioxidant, and anti-tumor properties. However, the poor stability, fragile chemical structure, and high hydrophilicity of CC seriously affect the ultimate anti-tumor effect of the drug. In order to overcome these drawbacks of CC, berberine (BBR) assisted CC assembly with the same anti-cervical cancer effect was selected, taking advantage of the easy alkaloid self-assembly properties of polyphenolic compounds. We report a novel dual component (BBR and CC) directed self-assembly mode. The two small molecules were assembled into highly drug-loaded, homogeneous supramolecules (341 nm) by π-π stacking at 60℃, pH 7.4, the reaction time of 1 h, and the molar ratio of BBR to CC of 2:1. The supramolecular self-assembled nanoparticles (NPS) not only exhibit excellent stability, high assembly rate (86.42 %), and sustained release performance, but also have stronger cell binding and uptake capabilities. In addition, the assembled supramolecules (BBR-CC NPS) retain the excellent biological characteristics of BBR and CC. It had good anti-inflammatory and antioxidant effects. More importantly, this NPS can disrupt mitochondrial membrane potential, increase reactive oxygen species (ROS) release, and induce apoptosis in cancer cells. These results indicated that BBR-CC NPS can serve as a carrier-free drug delivery system that enhances drug stability while exhibiting synergistic pharmacological activity. This provides more possibilities for the application of natural small molecules in cancer treatment and drug delivery. Additionally, it also presents new insights into the integration mechanism of traditional Chinese medicine. [Display omitted] [ABSTRACT FROM AUTHOR]

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway. [Display omitted] • Hippo signaling pathway is emerged an attractive target for the development of anticancer agents. • Small molecule inhibitors of Hippo signaling pathway demonstrated promising anticancer activity. • The strategies that regulate Hippo signaling pathway were discussed and summarized. [ABSTRACT FROM AUTHOR]

Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium , exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT. [Display omitted] • Design and synthesis of a series of novel carbamate prodrugs of cycloicaritin. • They improved water solubility, phase II metabolic stability, and 4b enhanced membrane permeability via active transport. • 4b showed satisfactory in vitro stability and activation to cycloicaritin in the blood. • 4b significantly increased the oral bioavailability of cycloicaritin and exerted good antitumor activity and safety. [ABSTRACT FROM AUTHOR]

• Cardiac glycosides (CGs) have been used for heart disease treatment. • We reviewed clinical studies on CGs for different cancer types in the past five years. • We highlighted both the strengths and limitations of CGs in cancer treatment. • Customizing the dosage and molecular testing of CGs are prospects for their use in cancer treatment. • Repurposing CGs for cancer requires attention to specific CGs and cancer types. Cardiac glycosides (CGs), which are traditionally used for heart disease, show promise for cancer therapy. However, there is a lack of a comprehensive review of clinical studies in this area, and so far, CGs have not been widely integrated into clinical cancer treatment. This review covers clinical studies from the past five years, highlighting the potential of CGs to reduce cancer risk, enhance chemotherapy effectiveness, mitigate chemotherapy-induced side effects and improve quality of life. Future clinical trials should personalize the dosage of CGs, integrate molecular testing and investigate immunogenic cell death induction and the potential of CGs for treating bone cancer and metastasis. Optimizing the repurposing of CGs for anticancer treatment requires consideration of specific CGs, cancer types and concurrent medications. [ABSTRACT FROM AUTHOR]

Breast and gynecological cancers are major health concerns due to their increasing incidence rates, and in some cases, their low survival probability. In recent years, multiple compounds of natural origin have been analyzed as alternative treatments for this disease. For instance, Acetogenins are plant secondary metabolites from the Annonaceae family, and its potential anticancer activity has been reported against a wide range of cancer cells both in vitro and in vivo. Several studies have demonstrated promising results of Acetogenins' antitumor capacity, given their selective activity of cellular inhibition at low concentrations. This review outlines the origin, structure, and antineoplastic activities in vitro and in vivo of Acetogenins from Annonaceae against breast cancer and gynecological cancers reported to date. Here, we also provide a systematic summary of the activity and possible mechanisms of action of Acetogenins against these types of cancer and provide references for developing future therapies based on Acetogenins and nanotechnologies. [Display omitted] • Acetogenins show anticancer effects in gynecological and breast cancers. • Compounds like bullatacin, annonacin, and bullacin B show potent anticancer activity. • The acetogenins interrupt the respiratory chain by inhibiting mitochondrial complex I. • The Bis-THF acetogenins demonstrate stronger anticancer activities. • The use of nanosystems to administer acetogenins enhances drug efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] • 3-O-β-D-galactosylated resveratrol (Gal-Res) polydopamine nanoparticles (Gal-Res NPs) can significantly improve the anti-tumor efficiency of Gal-Res and is a potential anti-tumor drug delivery system. Gal-Res NPs could significantly inhibit the migration and invasion abilities of HepG2 cells, and significantly induce apoptosis. • The mechanism of the anti-tumor effect of Gal-Res NPs is regulates the Bcl-2/Bax and AKT/GSK3β/β-catenin signaling pathways. In our previous studies, 3-O-β-D-galactosylated resveratrol (Gal-Res) was synthesized by structural modification and then 3-O-β-D-galactosylated resveratrol polydopamine nanoparticles (Gal-Res NPs) were successfully prepared to improve the bioavailability and liver distribution of Res. However, the pharmacodynamic efficacy and specific mechanism of Gal-Res NPs on hepatocellular carcinoma remain unclear. Herein, liver cancer model mice were successfully constructed by xenograft tumor modeling. Gal-Res NPs (34.2 mg/kg) significantly inhibited tumor growth of the liver cancer model mice with no significant effect on their body weight and no obvious toxic effect on major organs. Additionally, in vitro cellular uptake assay showed that Gal-Res NPs (37.5 μmol/L) increased the uptake of Gal-Res by Hepatocellular carcinoma (HepG2) cells, and significantly inhibited the cell migration and invasion. The experimental results of Hoechst 33342/propyl iodide (PI) double staining and flow cytometry both revealed that Gal-Res NPs could remarkably promote cell apoptosis. Moreover, the Western blot results revealed that Gal-Res NPs significantly regulated the Bcl-2/Bax and AKT/GSK3β/β-catenin signaling pathways. Taken together, the in vitro/in vivo results demonstrated that Gal-Res NPs significantly improved the antitumor efficiency of Gal-Res, which is a potential antitumor drug delivery system. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a significant global health concern, with high rates of morbidity and mortality. Bucidarasin A, a natural diterpenoid, has been shown to exert notable cytotoxic effects across a range of tumor cell lines. However, the underlying mechanisms responsible for this cytotoxicity remain unclear. In this study, we sought to elucidate the antitumor mechanisms of bucidarasin A, a natural diterpenoid derived from Casearia graveolens , with a particular focus on its effects on HCC. Furthermore, we employed surface plasmon resonance (SPR), molecular docking, and cellular thermal shift assay (CETSA) to gain further insight into the target protein of bucidarasin A. Our findings revealed that bucidarasin A exhibited pronounced cytotoxicity towards HepG2 cells. In vitro analysis indicated that bucidarasin A interrupted the cell cycle at the S phase and inhibited the proliferation and metastasis of HepG2 cells by modulating the FAK and STAT3 signaling pathways. Moreover, in vivo studies demonstrated that bucidarasin A not only exhibited antitumor effects but also impeded neovascularization, a finding that was corroborated by SPR interactions between vascular endothelial growth factor (VEGF) and bucidarasin A. This research substantiated that bucidarasin A, a clerodane diterpenoid, held promise as a therapeutic candidate against HCC, showcasing substantial antitumor efficacy both in vitro and in vivo through direct targeting of the STAT3 and FAK signaling pathways. [Display omitted] • The mechanism of bucidarasin A in the treatment of HCC was elucidated. • Bucidarasin A could inhibit the proliferation and migration of HepG2 cells in vitro and in vivo. • The target protein of bucidarasin A was confirmed. • Bucidarasin A could inhibit the formation of new vessels in vivo. [ABSTRACT FROM AUTHOR]

Enzyme-activatable drug delivery systems have been developed for cancer diagnosis and therapy. However, targeted intracellular drug delivery is a challenge for precisely tumor imaging and therapy due to the increased stability of copolymer nanoparticles (NPs) is accompanied by a notable decrease in enzyme degradation. Herein, disulfide bond was designed as an enzyme-activatable molecular switch of SS-P(G 2) 2 /DOX NPs. The copolymer NPs consists of polyvinylpyrrolidone (PVP) with disulfide bonds in the center and enzyme-degradable peptide dendrites (Phe-Lys) to form dendritic-linear-dendritic triblock copolymers (TBCs). The amphiphilic TBCs could be split into two identical amphiphilic diblock copolymers (DBCs) by glutathione (GSH) in cancer cells specifically while maintaining the same hydrophilic-lipophilic equilibrium. This structural transformation significantly reduced the stability of copolymer NPs and enhanced sensitivity of DOX release by cathepsin B-activated. Subsequently, the released DOX acted as an indicator of fluorescence imaging and chemotherapy drug for cancer cells. The polymeric NPs achieved excellent drug-loaded stability and prolonged blood circulation in vivo , and realized fluorescence imaging and specific cancer cell killing capabilities by responding to the overexpression of GSH and cathepsin B in tumor cells. Furthermore, the copolymer NPs demonstrated excellent blood compatibility and biosafety. Therefore, a novel strategy based on one tumor marker acting as the switch for another tumor microenvironment responsive drug delivery system could be designed for tumor intracellular imaging and chemotherapy. A highly stable hydrophobic-hydrophilic-hydrophobic three blocks copolymer nanocarriers with the disulfide bond in the center has been designed to respond by tumor-overexpressed GSH, and transform into half molecular weight and enzyme-accessible diblock copolymer nanocarrier. This design enhanced drug-loaded stability of NPs and prolonged blood circulation in vivo , and realized specific fluorescence imaging and antitumor activity by responding to the overexpression of GSH and cathepsin B in tumor cells. [Display omitted] • SS-P(G 2) 2 amphiphilic triblock copolymers of SS-P(G 2) 2 with disulfide bonds as enzyme activity switch were prepared. • The enzyme-activitable drug release of SS-P(G 2) 2 /DOX NPs was activied by reducing the assembly stability. • SS-P(G 2) 2 /DOX NPs achieved cathepsin B-activatable DOX release with GSH treatment. • Biocompatible, excellent tumor targeting, specific fluorescence imaging capability and antitumor activity in vivo were confirmed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two families of N -cinnamoyl-aminoacridine conjugates are proposed as antiproliferative leads. • One family of conjugates showed in vitro activity against three cancer cell lines in the micromolar range. • Two conjugates showed better antiproliferative activity in vitro than reference drugs. • The most promising conjugates were highly selective, showing no toxicity to non-carcinogenic cells. Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans- cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N -cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • Thirteen novel benzodioxolane compounds were designed and synthesized. • HJ1 emerged as the most potent compound, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies. [ABSTRACT FROM AUTHOR]

• Two novel sets of thiohydantoin derivatives were designed and synthesized with expected cytotoxicity and androgen antagonists based on the binding pattern of enzalutamide to the androgen receptor. • The dicyanide derivatives 3a showed the best LNCaP inhibition demonstrating IC 50 of 2.64 µM with a potential to inhibit its S-phase reducing the natural DNA transactivation of androgens. • In vivo evaluation of 3a significantly ameliorated the testosterone-induced increase in the prostate index and weight as compared to finasteride. • Apoptosis initiation was observed in the early phase with 22.74 % in contrast to 9.06 % at the late phase with respect to 0.44 % and 0.13 % of the control cells at early and late stages, respectively. Novel thiohydantoin derivatives were designed as androgen antagonists based on the binding pattern of enzalutamide to the androgen receptor that avoided the bifurcated activation pattern of dihydrotestosterone. Twelve thiohydantoin derivatives were synthesized following Michael-type addition which were fully characterized. The dicyanide derivatives 3a showed the best LNCaP inhibition demonstrating IC 50 of 2.64 µM with a potential to inhibit its S-phase reducing the natural DNA transactivation of androgens. Moreover, apoptosis initiation was observed in the early phase with 22.74 % in contrast to 9.06 % at the late phase with respect to 0.44 % and 0.13 % of the control cells at early and late stages, respectively. In vivo evaluation of 3a significantly ameliorated the testosterone-induced increase in the prostate index and weight as compared to finasteride. This was confirmed by the histopathological examinations of prostatic tissues that demonstrated a reduction in the accompanied histopathological changes as well as lowering the immunohistochemical up-regulation of androgen receptors induced by testosterone. Moreover, molecular docking simulation justified the achieved biological activity. [Display omitted] [ABSTRACT FROM AUTHOR]

• A novel series of isoxazoline derivatives were synthesized and characterized. • The structure of compound 8a was confirmed by single crystal X-ray diffraction. • Theoretical calculations by DFT were studied. • Compounds (8a-8k) showed notable antitumor activity against A549 cells. The isoxazolidine skeleton is an important component of biologically active natural products, and many compounds containing isoxazolidine ring exhibit excellent antibacterial and anticancer activities. Based on the variously biological activity of isoxazolidines, a new series of isoxazolidine derivatives were designed and synthesized. All the structure of target compounds was characterized by NMR and HRMS. Especially, compound 8a ((Z)-2-methyl-4-(phenoxymethylene)-3-phenylisoxazolidine) was prepared for single crystal X-ray diffraction and FT-IR. Density functional theory (DFT) calculations were also performed on compound 8a at the B3LYP/6–311 level. In addition, after evaluation with MTT method of compounds 8a-8k against A549 cells, it was found that some compounds performed well antitumor activities. [ABSTRACT FROM AUTHOR]

• The synthesis of benzophenone is accompanied by the conversion of CH 3 O- to HO-. • Benzophenone compounds exhibited very strong inhibitory activity against HL-60 cells. • Network pharmacology and molecular docking are valuable tools for drug discovery. Using Eaton's reagent or boron trifluoride ether, 24 compounds were synthesized in a 1- or 2-step reaction, with the conversion of the methoxy group to the hydroxyl group. Next, the in vitro antitumor activity of all compounds and the antioxidant activity of compounds 1 to 3 were investigated. Compounds 7, 13, 15, 17, 18, 20, 22 , and 24 exhibited strong antitumor activity and were considered promising compounds. Among them, compounds 7, 13 , and 18 exhibited very strong inhibitory activity against HL-60 cells with IC 50 values of 0.55, 0.29, and 0.72 μM, respectively. Furthermore, compounds 1 to 3 exhibited moderate antioxidant activity and their mechanism of action was further validated by computational chemistry. Finally, the antitumor mechanism of the above 8 compounds was investigated through network pharmacology and molecular docking, and 19 key genes and 20 pathways were obtained. These results will allow future development of benzophenone and its derivatives. [Display omitted] [ABSTRACT FROM AUTHOR]

An efficient Brønsted acid catalyzed formal (3 + 2) annulation reactions of 3-hydroxy-3-phenacyloxidole derivatives with 2-naphthols and activated phenols has been developed. This formal (3 + 2) annulation involved a dehydration/Friedel-Crafts alkylation/hemiketalization/dehydration cascade process, and afforded a variety of highly functionalized oxindolyl-naphthofurans with good yields. Moreover, some of the obtained products were tested against a panel of cancer cell lines, and one compound was identified to inhabit the proliferation of some cancer cell lines, thus indicating that such skeletons might server as leading compounds with antitumor activity. [Display omitted] • A formal (3 + 2) annulation reaction of 3-hydroxy-3-phenacyloxidole derivatives with 2-naphthols and activated phenols was established by the Brønsted acid catalyst. • This formal (3 + 2) annulation involved a dehydration/Friedel-Crafts alkylation/hemiketalization/dehydration cascade process, the strategy allowed the preparation of highly functionalized oxindolyl-naphthofuran scaffolds. • Moreover, we have done the bioactivity evaluation of the compounds, and one of the obtained products was identified to inhibit the proliferation of some cancer cell lines, thus indicating that such skeletons might serve as leading compounds for the development of antitumor drugs. • In situ construction of diverse oxindolyl-naphthofuran scaffolds with moderate to high yields. One of the products can inhibit the proliferation of some cancer cell lines. [ABSTRACT FROM AUTHOR]

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N -indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7–109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G 2 /M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development. [Display omitted] • N -indolyl-3,4,5-trimethoxybenzenesulfonamides are potent anti-mitotics. • Different tumour cell-lines show different sensitivities. • Compounds cause G 2 /M cell cycle arrest and induction of apoptosis. • The substituent on the sulfonamide determines mechanism and cell fate. • Binding at the colchicine site of tubulin. [ABSTRACT FROM AUTHOR]

A series of tetrahydroisoquinolines ammonium salt derivatives were synthesized and showed good inhibitory activities against the cancer cell lines of HCT116, MDA-MB-231, HePG2, and A375. [Display omitted] • A series of tetrahydroisoquinolines ammonium salt derivatives were designed and synthesized. • The compounds showed much higher inhibitory activities against the cancer cell lines of HCT116, MDA-MB-231, HePG2, and A375 (IC 50 2.5–5.4 μM) than noscapine. • Molecular docking results indicated that there were hydrogen bonding interaction, ionic interaction and pi-H interaction between compound and 5JWK protein. Cancer, as a public health issue, is the leading cause of death worldwide. Tetrahydroisoquinoline derivatives have effective biological activities and can be used as potential therapeutic agents for antitumor drugs. In this work, we designed and synthesized a series of novel tetrahydroisoquinoline compounds and evaluated their antitumor activity in vitro on several representative human cancer cell lines. The results showed that the vast majority of compounds showed good inhibitory activities against the cancer cell lines of HCT116, MDA-MB-231, HepG2, and A375. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis and characterisation of twelve new substituted 3,4-dihydro-2 H -1,4-benzoxazine derivatives. • Compounds 2b and 4b showed promising antiproliferative activity against MCF-7 breast cancer and HCT-116 colon cancer cell lines. • 2b and 4b displayed a consistent binding mode to hHER2 and hJNK1 kinases. • 2b and 4b exhibited potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. • In the HCT-116 cell line, 2b and 4b arrest the cell cycle in the S phase. The search for new agents targeting different forms of cell death is an important research focus for developing new and potent antitumor therapies. As a contribution to this endeavor, we have designed and synthesized a series of new substituted 3,4-dihydro-2 H -1,4-benzoxazine derivatives. These compounds have been evaluated for their efficacy against MCF-7 breast cancer and HCT-116 colon cancer cell lines. Overall, substituting this heterocycle led to improved antiproliferative activity compared to the unsubstituted derivative 1. The most active compounds, 2b and 4b , showed IC 50 values of 2.27 and 3.26 μM against MCF-7 cells and 4.44 and 7.63 μM against HCT-116 cells, respectively. To investigate the mechanism of action of the target compounds, the inhibition profile of 8 kinases involved in cell signaling was studied highlighting residual activity on HER2 and JNK1 kinases. 2b and 4b showed a consistent binding mode to both receptor kinases, establishing significant interactions with known and catalytically important domains and residues. Compounds 2b and 4b exhibit potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. This dual capability increases their versatility in the treatment of different stages or types of tumors, providing greater flexibility in clinical applications. [ABSTRACT FROM AUTHOR]

In the past several decades, N -heterocyclic carbene (NHC) ligands with strong σ donation have become of great interest for transition metal medicinal applications. This review mainly focuses on an update of transition metal–NHC complexes in antitumor therapy, including the antitumor properties, the possible mechanisms of action, and structure–activity relationships for novel metal–NHC complexes from 2017 to the present. [Display omitted] • Recent developments of transition metal N-heterocyclic carbene (NHC) complexes for antitumor therapy are reviewed. • The antitumor properties of metal–NHC complexes (Au, Ag, Pd, Pt, Ru, Rh, Re, Ir, Fe, Cu) are discussed. The structure–activity relationships and possible mechanisms of action are summarized. Metal complexes, which exhibit alterable oxidation states, coordination numbers, and capacity to coordinate with different ligands, have provided a versatile platform for designing novel theranostic agents. By optimizing ligands, the curative effect of metal ions can be improved by the suitable stability and spatial configuration to act with the therapeutic target. In the past several decades, N -heterocyclic carbene (NHC) ligands with strong σ donation have become of great interest for transition metal (Au, Ag, Pt, etc.) medicinal applications. The research on metal–NHC (M−NHC) complexes as potential antitumor metallodrugs has been boosted dramatically since the seminal research by Berners-Price et al. in 2004. This review provides the latest advances in NHC-based metallodrugs from 2017 to the present. The antitumor properties, possible mode of action, and structure–activity relationships for NHC metallodrugs are summarized. We hope this comprehensive review will be of great benefit to researchers designing novel M−NHC antitumor drugs and developing metallodrugs for successful clinical application. [ABSTRACT FROM AUTHOR]

The conventional silver nanoparticles (Ag NPs) are characterized with high loading rate and stacking phenomenon, leading to shedding caused biotoxicity and low catalytic efficiency. This seriously hinders their application in biomedicine. Here, we modified the highly dispersible Ag NPs and Ag single-atoms (SAs) synthesis by combining the halloysite clay nanotubes (HNTs) and dodecahydro-dodecaborate (closo- [B 12 H 12 ]2–) to increase the biocompatible properties and decrease the loading rate. This novel Ag single-atom nanoenzyme alongside Ag NPs nanoenzyme avoid the elevated-temperature calcination while maintaining the exceptionally high-level efficiency of Ag utilization via the reducibility and coordination stabilization of closo -[B 12 H 12 ]2− and HNTs. With theoretical calculation and electron paramagnetic resonance, we confirmed that both Ag SAzymes and Ag NPs in HNT@B 12 H 12 @Ag nanoenzyme are capable decompose the H 2 O 2 into hydroxyl radical (·OH). For the application, we investigated the catalytic activity in the tumor cells and antitumor effects of HNT@B 12 H 12 @Ag nanoenzyme both in vitro and in vivo , and confirmed that it effectively suppressed melanoma growth through ·OH generation, with limited biotoxicity. This study provides a novel Ag nanoenzyme synthesis approach to increase the possibility of its clinical application. • Ag nanoparticles were synthesized via [ closo- B 12 H 12 ]2− and halloysite (HNT). • HNT@B 12 H 12 @Ag have the robust ability to decompose H 2 O 2 to ·OH. • HNT@B 12 H 12 @Ag with excellent biocompatibility. • HNT@B 12 H 12 @Ag effectively inhibits tumor growth through the generation of ·OH. [ABSTRACT FROM AUTHOR]

In order to reduce the cardiotoxicity of doxorubicin (DOX) and improve its antitumor effect, dihydroartemisinin (DHA) and DOX prodrug (DOX-S-DHA) synthesized via a single sulfur bond was used with TEPP-46 to prepare nano-liposomes (DOX-S-DHA@TEPP-46 Lips). In which, TEPP-46 was expected to exert p53 bidirectional regulation to promote the synergistic antitumor effect of DOX and DHA while reducing cardiotoxicity. DOX-S-DHA@TEPP-46 Lips exhibited uniform particle size, good stability, and excellent redox-responsive activity. DOX-S-DHA@TEPP-46 Lips could significantly inhibit the proliferation of tumor cells, but had less cytotoxicity on normal cells. The presence of TEPP-46 increased the content of p53 protein, which further induced tumor cell apoptosis. DOX-S-DHA@TEPP-46 Lips had satisfactory long circulation to enhance the antitumor efficacy and reversed the cardiotoxicity of DOX in B16-F10 tumor-bearing mice. In conclusion, DOX-S-DHA@TEPP-46 Lips provides a new insight on creating sophisticated redox-sensitive nano-liposomes for cancer therapy as well as the decreased cardiotoxicity of DOX. [Display omitted] • DOX-S-DHA was synthesized to exert the combined effect of DOX and DHA. • TEPP-46 could promote the synergistic effect of DOX and DHA at the tumor site. • TEPP-46 could reduce the cardiotoxic effect through p53 bidirectional regulation. [ABSTRACT FROM AUTHOR]