Inhibit Cancer Cell Growth Research Articles

Electrochemistry and in-situ spectroelectrochemistry properties of N-, S-substituted-1,4-naphthoquinone compounds (NQ’s)

Quinones are ubiquitous in nature and form one of the largest classes of antitumor agents approved for clinical use. Naphthoquinones and their derivatives are important in many fields such as pharmaceutical, medical, and environmental applications. It is also known that such compounds show strong biological activity against various bacteria, viruses, fungi, and cancer cells. They are known to be efficient in inhibiting cancer cell growth. Under physiological conditions, they can undergo non-enzymatic one-electron reduction to give the moderately toxic species of semiquinone radical-anion. Thus, the electrochemical study of quinones might provide a basic knowledge of semi-quinone radical formation in both in vivo and in vitro under different media.In this study, firstly, novel N-, S- and/or halo(Br/Cl)-substituted-1,4-naphthoquinone derivatives (2a-d, 3e, 4, 6a-f, 7, 8 and 9) were synthesized. The structures of all compounds were elucidated by using spectroscopic methods [FT-IR, NMR (1H/13C), MS, and microanalysis]. Electrochemical characterization indicated that all compounds underwent two well-resolved reduction reactions assigned to NQ/NQ.− and NQ.−/NQ2− processes respectively. Additionally, an all-defined irreversible oxidation wave was also recorded for all compounds. The substituents on the NQ ring altered the peak position and reversibility of the electron transfer reactions. Redox processes considerably influenced the spectra of the compounds which showed different colors and spectra for different electrogenerated anionic and cationic forms of the compounds.

Azacitidine Combined with Novel Flavonoid Derivative GL-V9 Demonstrated Synergistic Anti-Leukemia Effect in Acute Myeloid Leukemia By Targeting DDIT4/mTOR Signaling

Background Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of malignant progenitor cells and impaired cell differentiation. GL-V9, a nature compound derived from wogonin, has shown superior anti-tumor potential by inhibiting cancer cell growth. Azacitidine (AZA), a DNA hypomethylation agent, has demonstrated therapeutic efficacy against AML. In this study, we investigated the anti-leukemia effect and potential mechanism of AZA combined with GL-V9 in AML cells, aiming to provide evidence for future clinical treatment. Methods We employed Cell Counting Kit-8 (CCK-8) to assess cell viability, Annexin-V/PI staining followed by flow cytometry analysis to measure apoptosis. CalcuSyn analysis was used to evaluate the synergistic effect. RNA-seq was performed in U937 cells and differentially expressed genes (DEGs) were identified and subjected to KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. RT-qPCR and Western Blot were used to examine gene expression. Results Our results demonstrated significant cell proliferation arrest in U937 and MV4-11 cells treated with the combination of AZA and GL-V9, compared to the single drug ( Fig. 1A&B). CalcuSyn analysis showed a strong synergistic effect for the combination ( Fig. 1A&B). Similar results were also found in primary AML cells derived from 2 AML patients [patient 1 exhibited t(6;11) (q27;q23) chromosomal translocation, while Patient 2 presented with secondary AML, transformed from CMML (Chronic Myelomonocytic Leukemia) and featured ASXL1 and SRSF2 mutations] ( Fig. 1C&D). Moreover, AZA plus GL-V9 induced a substantial increase in cell apoptosis in U937 and MV4-11 cells compared to the single drug ( Fig. 1E&F). Consistently, the AZA+GL-V9 combination led to a notable increase in the protein level of Bax, BAD, BIM, and a decrease in BCL2 ( Fig. 1G). These data indicated the combination of AZA with GL-V9 has synergistic anti-leukemia effects in AML. To understand the underlying mechanisms of this synergy, we performed RNA-seq analysis in U937 cells, identifying 1385 and 586 DEGs (|log 2FC|≥2.0, P<0.05) upon AZA or GL-V9 treatment, respectively ( Fig. 2A). The mTOR signaling pathway exhibits prominent enrichment in the KEGG analysis of the overlapping DEGs between AZA and GL-V9 ( Fig. 2B). DDIT4, a negative regulator of mTOR emerged as one of the top DEGs in response to both AZA and GL-V9 treatment. Importantly, the AZA+GL-V9 treatment exhibited a higher expression level of DDIT4 compared to either drug alone and suppressed the phosphorylation of mTOR ( Fig. 2C). Additionally, the DDIT4 expression level was significantly decreased in AML patients, which derived from a public database (TCGA-AML, GSE13159)] ( Fig. 2D) and Zhongda Hospital (Nanjing, China) compared to the healthy controls ( Fig. 2E). To be noticed, high DDIT4 expression was associated with extended overall survival (P=0.021) ( Fig. 2F) and relapse-free survival (P=0.015) ( Fig. 2G), indicating DDIT4 may act as a tumor suppressor in AML. These findings suggested that the combination may exert the anti-leukemia effect by targeting the DDIT4/mTOR signaling pathway, as summarized in Fig. 2H. Conclusions Our study provides novel evidence of the synergistic effect on cell growth arrest and apoptosis treated with a new nature compound derived from wogonin combined with AZA in AML. Furthermore, we identified the mechanism underlying the synergy through targeting of DDIT4/mTOR signaling. These results offer preliminary support for the potential application of this combination therapy in treating AML patients.

Effect of Calcitriol in Inhibiting the Cancer Cell Growth and Promoting Apoptosis in ErbB2-positive Breast Cancer Cells.

Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment. The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib. We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene. The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2- positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib. The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option.

Targeting PPARγ/ NF-κB Signaling Pathway by Britannin, a Sesquiterpene Lactone from Inula aucheriana DC., in Gastric Cancer.

Gastric cancer is one of the most common and deadliest malignancies in the world. Therefore, there is an urgent need to develop new and effective agents to reduce mortality. The plants of genus Inula have gained the attention of researchers worldwide as a rich source of potent medicinal compounds. This study explores the anti-cancer activity of Britannin, a sesquiterpene lactone isolated from Inula aucheriana DC., and its molecular mechanism in gastric cancer cells, AGS and MKN45. Cytotoxicity was evaluated through the MTT assay following 24 h, 48 h, and 72 h treatment with different concentrations of Britannin. Apoptosis rate and caspase-3 activity were measured 24 h after treatment by Britannin. . Western blotting was performed to determine the expression of the NF-κB, IκBα, and PPARγ proteins. Moreover, quantitative RT-PCR was applied to measure the expression of NF-κB target genes. We showed that Britannin induced cell growth inhibition and apoptosis in gastric cancer cells. Britannin caused an elevation in mRNA and protein levels of PPARγ. The involvement of PPARγ was more confirmed using GW9662, a PPARγ inhibitor. Suppression of NF-κB was demonstrated by western blot analysis. Down-regulation of MMP-9, TWIST-1, COX-2, and Bcl-2 and up-regulation of Bax were also observed in gastric cancer cells. These results imply that activation of the PPARγ signaling pathway through suppression of NF-κB underlies the anti-cancer properties of Britannin in gastric cancer. Therefore, Britannin could be considered as a promising anti-cancer candidate for further evaluation.

TAS0612, a Novel RSK, AKT, and S6K Inhibitor, Exhibits Antitumor Effects in Preclinical Tumor Models.

The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.

A non-canonical role of endothelin converting enzyme 1 (ECE1)in promoting lung cancer development via directly targetingprotein kinase B (AKT).

Lung cancer is the second most common malignancy in the world, and lung adenocarcinoma (LUAD) in particular is the leading cause of cancer death worldwide. Endothelin converting enzyme 1 (ECE1) is a membrane-bound metalloprotease involved in endothelin-1 (ET-1) processing and regulates vasoconstriction. However, very few studies have reported the involvement of ECE1 in regulating tumor cell proliferation, and the mechanism remains poorly understood. Therefore, we aimed to determine the role of ECE1 in lung cancer development. The Cancer Genome Atlas database and Kaplan-Meier plotter were used to assess the association between ECE1 and lung cancer. The expression of ECE1 was detected using immunohistochemistry staining and western blotting. A variety of in vitro assays were performed to evaluate the effects of ECE1 on the colony formation, proliferation, migration and invasion using ECE1 knockdown lung cancer cells. The gene expression profiles regulated by ECE1 were investigated by RNA sequencing. An immunoprecipitation assay and immunofluorescence assay were used to evaluate the mechanism underlying the regulatory effect of ECE1 on protein kinase B (AKT). The effect of ECE1 on tumor development was assessed by xenografted lung cancer cells in either C57BL/6 mice or nude mice. ECE1 was upregulated in LUAD and correlated with the poor prognosis of patients with LUAD. Functional studies showed that knockdown of ECE1 retarded the progression of tumors formed by lung cancer cells at least partly by inhibiting tumor cell proliferation. Moreover, ECE1 accelerated tumor cell proliferation through promoting AKT activation dispensable of its canonical target ET-1. Mechanically, ECE1 interacted with the pleckstrin homology (PH) domain of AKT and facilitated its translocation to the plasma membrane for activation. Furthermore, the inhibition of AKT activity counteracted the lung cancer cell growth inhibition observed both in vitro and in xenografts caused by ECE1 suppression. The present study reveals a non-canonical function of ECE1 in regulating AKT activation and cell proliferation, which provides the basis for the development of a novel strategy for the intervention of cancer including LUAD by abrogating ECE1-AKT signaling.

Ancient forest plants possess cytotoxic properties causing liver cancer HepG2 cell apoptosis

Here, we collected 154 plant species in China ancient forests looking for novel efficient bioactive compounds for cancer treatments. We found 600 bioactive phyto-chemicals that induce apoptosis of liver cancer cell in vitro. First, we screen the plant extract's in vitro cytotoxicity inhibition of cancer cell growth using in vitro HepG2 cell lines and MTT cytotoxicity. The results from these initial MTT in vitro cytotoxicity tests show that the most efficient plants towards hepatoma cytoxicity is Cephalotaxus sinensis, mint bush (Elsholtzia stauntonii) and winged spindle tree (Euonymus alatus). We then used in cell-counting kit-8 (CCK-8) to further understand in vivo tumor growth using nude mice and GC-MS and LC-QTOF-MS to analyze the composition of compounds in the extracts. Extracted chemically active molecules analyzed by network pharmacology showed inhibition on the growth of liver cancer cells by acting on multiple gene targets, which is different from the currently used traditional drugs acting on only one target of liver cancer cells. Extracts from Cephalotaxus sinensis, mint bush (Elsholtzia stauntonii) and winged spindle tree (Euonymus alatus) induce apoptosis in hepatoma cancer cell line HepG2 with a killing rate of more than 83% and a tumor size decrease by 62–67% and a killing rate of only 6% of normal hepatocyte LO2. This study highlight efficient candidate species for cancer treatment providing a basis for future development of novel plant-based drugs to help meeting several of the UN SDGs and planetary health.

Effects of Patterned Electromagnetic Fields and Light-Emitting Diodes on Cancer Cells: Impact on Cell Density and Biophoton Emission When Applied Individually vs. Simultaneously

It has been previously reported that time-varying EMFs and LEDs have the potential to modulate cellular activity and cell viability. It has also been shown that cellular activity and state can be inferred by measuring the biophoton emission derived from these same cells. To identify if the brief application (15 min) of an LED (635 nm at 3 klx) or EMF (1–3 uT) could influence cell growth and subsequent biophoton emission characteristics, B16-BL6 cells were grown to confluence and exposed to a time-varying, frequency-modulated EMF, LED, or both. Before and after EMF and LED exposure, photon emission measurements were taken for 1 min at a 50 Hz sampling rate. Following the exposure and photon emission measurements, cell viability was assessed via the use of a hemocytometer. The results demonstrated that after only 15 min of exposure to a time-varying EMF, there was a 41.6% reduction in viable cells when compared to sham controls [t(25) = 2.4, p = 0.02]. This effect approached significance in the LED alone condition [p = 0.07] but was completely absent in the condition wherein the LED and EMF were applied simultaneously [p < 0.8]. Additionally, following exposure to only the LED, there was a significant increase in biophoton emission SPD values at 13 Hz from whole cell cultures [t(60) = 2.3, p = 0.021]. This biophoton emission frequency was also strongly correlated with the number of nonviable cells [r = −0.514] in the dish. Taken together, these data point to biophotons emitted from cell cultures at 13 Hz as a potential indicator of the number of nonviable cells in vitro. The summation of data here corroborates previous work demonstrating the efficacy of specific time-varying EMFs as a novel therapeutic for the inhibition of cancer cell growth. It also furthers our assertion that biophoton emission can be used as a novel detection tool for cell activity.

Ellagic Acid from Hull Blackberries: Extraction, Purification, and Potential Anticancer Activity.

Ellagic acid (EA) is present at relatively high concentrations in many berries and has many beneficial health effects, including anticancer properties. To improve the development and utilization of blackberry fruit nutrients, we divided Hull blackberry fruits into five growth periods according to color and determined the EA content in the fruits in each period. The EA content in the green fruit stage was the highest at 5.67 mg/g FW. Single-factor tests and response surface methodology were used to optimize the extraction process, while macroporous resin adsorption and alkali dissolution, acid precipitation, and solvent recrystallization were used for purification. The highest purity of the final EA powder was 90%. The anticancer assessment results determined by MTT assay showed that EA inhibited HeLa cells with an IC50 of 35 μg/mL, and the apoptosis rate of the cells increased in a dose-dependent manner, with the highest rate of about 67%. We evaluated the changes in the mRNA levels of genes related to the EA-mediated inhibition of cancer cell growth and initially verified the PI3K/PTEN/AKT/mTOR pathway as the pathway by which EA inhibits HeLa cell growth. We hope to provide a theoretical basis for the deep exploration and utilization of this functional food.

Exploring the anti-cancer potential of methanolic extract from Simarouba glauca: Induction of apoptosis and growth inhibition in lung cancer cells

The causes behind lung cancer etiology remain unknown, and treatment failure is often caused by medication resistance, recurrence, and metastasis. Clinical development of novel therapeutic molecules to overcome drug resistance remains a problem. The purpose of this study was to evaluate the potential of Simarouba glauca triterpenoids among two different plant extracts (leaf extract and bark extract) in two human cell lines: lung adenocarcinoma (A549) and normal lung (L132) cell lines using four different solvents. The concentration yield of methanolic bark extract and leaf extracts was found to be higher compared to the other solvents using the Soxhlet method of extraction. Phytochemical analysis using Liberman-Burchard's test conducted confirmed the presence of triterpenoids in Methanolic extract from barks of Simarouba glauca. Comparative cytotoxicity potential among the extracts from bark and leaves, bark extracts showed an IC50 and LD50 as 350 μg/mL and 300 μg/mL respectively on the A549 cell lines of lung carcinoma. Cell cycle analysis using Methanolic bark extracts in comparison to the leaf extracts showed the arrest of the proliferation of A549 cells at the G0/G1 stage with a significant increase in cells at a level of 42.33%, 23.93%–23.47%, 17.96% respectively. Increased Reactive Oxygen Species (ROS) levels in the A549 cells in 1 h treated with bark extract and leaf extract than in the untreated cells. The methanolic extract from both the bark and leaves was found to be the most potent presenting potential arrest of cell cycle, reactive oxygen species generation and apoptosis. In summary, our study has found that the S. glauca-based plant extract has the anticancer potential by triggering apoptosis.

Effect of the bile salt surfactant sodium taurodeoxycholate on the physicochemical properties of a mixed system of Galangin-Hemoglobin and Baicalein-Hemoglobin

A surfactant that can regulate interactions between drugs and proteins would be a material that is medicinally excipient and biomimetic that has great theoretical and practical significance. Thus, the interactions and binding mechanism of flavonoid isomers [galangin (Gal) and baicalein (Bai)] and hemoglobin (HB) under physiological conditions were studied using multispectral methods, dynamic light scattering (DLS), and antioxidant, antibacterial, and cytotoxicity assay techniques. Then, one bile salt biosurfactant [sodium taurodeoxycholate (NaTDC)] was added to explore the effects that it has on the interactions and functional properties of Gal-HB and Bai-HB systems. For Gal-HB and Bai-HB systems, the fluorescence quenching mechanism of flavonoids on HB was always a static quenching. Driven mainly by electrostatic forces, the conformation of HB became loose, and its secondary structure changed as a result of the presence of Gal or Bai. Three adjacent hydroxyl groups on the A-ring had an obvious binding interaction with protein, and thus, Bai had a stronger binding affinity with HB than Gal, and this has a greater influence on the secondary structure of HB than Gal. In the presence of NaTDC, the binding constants were significantly increased for both systems; also, the antioxidant character, stability, solubility, antibacterial properties, and cancer cell growth inhibition of flavonoids were improved to a certain extent. These findings help us understand the pharmacokinetics, pharmacodynamic function and mechanism of Gal and Bai at the molecular level and also lay the scientific foundation for the design of flavonoid-based foods and drugs.

Anti-proliferative activity of chitosan-coated oxypeucedanin nano-chitosomes (COPD-NCs) against human HT-29 colon cancer cells: in vitro study.

Oxypeucedanin (OPD) as a powerful anti-proliferative agent found in the Angelicae dahuricae has been used to suppress cancer cell growth. However, the hydrophobic chemical structure has limited its solubility and bio-accessibility. This is the first time OPD is encapsulated into a nano-liposomal structure and coated with poly-cationic chitosan polymer as the oxypeucedanin drug delivery system to evaluate its antioxidant and anti-colon cancer potential. The chitosan-coated oxypeucedanin nano-chitosomes (COPD-NCs) were synthesized utilizing the thin-layer hydration method and characterized by FESEM, DLS, FTIR, and zeta potential analysis. The anti-cancer potential of COPD-NC was analyzed by measuring the cell survival rate (MTT assay) and studying the cellular death type (AO/PI staining) following the increased treatment concentrations of COPD-NC on the HT-29 colon cancer cell line. Moreover, the COPD-NCs' apoptotic activity was verified by analyzing Cas-3 and Cas-9 gene expression profiles. Finally, the COPD-NCs' antioxidant activity was evaluated by applying ABTS, DPPH, and FRAP antioxidant assays. The 258.26-nm COPD-NCs significantly inhibited the HT-29 colon cancer cells compared with the normal fibroblast HFF cells. The up-regulated Cas-3 and Cas-9 gene expression exhibited the COPD-NCs' apoptotic activity. Also, the COPD-NCs' apoptotic activity was verified by detecting the increased apoptotic bodies following the AO/PI fluorescent staining in the increased exposure doses of COPD-NCs. Ultimately, the COPD-NCs meaningfully inhibited the ABTS-DPPH radicals and exhibited an appropriate FRAP-reductive potential. The designed nanostructure for COPD-NCs significantly improved its antioxidant potential and selective cytotoxicity on human HT-29 human cancer cells, which makes them a safe selective natural drug delivery system. Therefore, the COPD-NCs can selectively induce apoptotic death in human HT-29 cancer cells and have the potential to be studied as an anti-colon cancer compound. However, further cancer and normal cell lines are required to verify their selective cytotoxicity.

CDC73 Impairment of MAPK1 Ubiquitination and Activation of the mTOR Signaling Pathway

CDC73 has been reported to be upregulated in breast cancer. This study aimed to illuminate the underlying mechanism by which CDC73 mediates breast cancer. Here, a breast cancer tissue microarray and three breast cancer cell lines MDA-MB-231, BT-549 as well as MCF-7 were employed. Using RNAi method, we knocked down CDC73 and MAPK1 in breast cancer cells. CDC73 overexpression plasmids (LV-013) were generated through pMD2.G and pSPAX2 vectors. Cell events related to tumor development were analyzed through Celigo cell counting assay, a cell counting kit, wound healing assay, Transwell assay and flow cytometry analysis. The exploration on the underlying mechanism was based on PrimeView human gene expression array. Xenograft tumor models were constructed to visualize the effects of CDC73/MAPK2 on breast cancer progression. CDC73 was abundantly expressed in breast cancer tissues and cell lines, and the expression of CDC73 was related to poor prognosis of patients. In breast cancer, CDC73 could promote the proliferation and migration of tumor cells, while disrupting apoptosis. Also, we found that CBL, an E3 ubiquitin ligase, could interact with CDC73 and promote MAPK1 ubiquitination and degradation of this protein. In addition, silencing MAPK1 led to a suppression of breast cancer cell growth in vitro and in vivo, and even abolished the promoting effects of CDC73 overexpression. We also found that mTOR pathway played a role in CDC73-mediated breast cancer. mTOR pathway inhibitor reversed cell phenotypes induced by CDC73 overexpression. CDC73 promoted MAPK1 ubiquitination and degradation so that affected MAPK1 level and subsequently led to breast cancer progression, providing a novel therapeutic strategy to combat cancer.

Cu2+ -Anchored Carbon Nano-Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis.

Both hydrogen (H2 ) and copper ions (Cu+ ) can be used as anti-cancer treatments. However, the continuous generation of H2 molecules and Cu+ in specific sites of tumors is challenging. Here we anchored Cu2+ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H2 and hydrogen peroxide (H2 O2 ) in tumors using the two-electron process of visible water splitting. The photocatalytic process also generated redox-active Cu-carbon centers. Meanwhile, the Cu2+ residues reacted with H2 O2 (the obstacle to the photocatalytic process) to accelerate the two-electron process of water splitting and cuprous ion (Cu+ ) generation, in which the Cu2+ residue promoted a pro-oxidant effect with glutathione through metal-reducing actions. Both H2 and Cu+ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal-enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.

Cu2+‐Anchored Carbon Nano‐Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis

AbstractBoth hydrogen (H2) and copper ions (Cu+) can be used as anti‐cancer treatments. However, the continuous generation of H2 molecules and Cu+ in specific sites of tumors is challenging. Here we anchored Cu2+ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H2 and hydrogen peroxide (H2O2) in tumors using the two‐electron process of visible water splitting. The photocatalytic process also generated redox‐active Cu‐carbon centers. Meanwhile, the Cu2+ residues reacted with H2O2 (the obstacle to the photocatalytic process) to accelerate the two‐electron process of water splitting and cuprous ion (Cu+) generation, in which the Cu2+ residue promoted a pro‐oxidant effect with glutathione through metal‐reducing actions. Both H2 and Cu+ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal‐enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.

Structural and functional characterization of USP47 reveals a hot spot for inhibitor design

USP47 is widely involved in tumor development, metastasis, and other processes while performing a more regulatory role in inflammatory responses, myocardial infarction, and neuronal development. In this study, we investigate the functional and biochemical properties of USP47, whereby depleting USP47 inhibited cancer cell growth in a p53-dependent manner—a phenomenon that enhances during the simultaneous knockdown of USP7. Full-length USP47 shows higher deubiquitinase activity than the catalytic domain. The crystal structures of the catalytic domain, in its free and ubiquitin-bound states, reveal that the misaligned catalytic triads, ultimately, become aligned upon ubiquitin-binding, similar to USP7, thereby becoming ready for catalysis. Yet, the composition and lengths of BL1, BL2, and BL3 of USP47 differ from those for USP7, and they contribute to the observed selectivity. Our study provides molecular details of USP47 regulation, substrate recognition, and the hotspots for drug discovery by targeting USP47.

Understanding of genes encoding bioactive compounds from potential medicinal plants in Indonesia as cancer cell inhibitors

Abstract. Muflikhati Z, Sianipar NF, Syamsunarno MRAA, Anas. 2023. Understanding of genes encoding bioactive compounds from potential medicinal plants in indonesia as cancer cell inhibitors. Biodiversitas 24: 4645-4660. Indonesia has abundant plant diversity and enormous potential to be developed as a source of medicinal plants due to the content of bioactive chemicals in them. Potential medicinal plants from Indonesia, such as Andrographis paniculata (Sambiloto), Curcuma longa (Kunyit), Moringa oleifera (Moringa), Phyllanthus niruri (Meniran), Orthosiphon stamineus (Kumis kucing), Typhonium flagelliforme (Keladi tikus), and Zingiber officinale (Jahe), contain bioactive compounds with mechanisms that act as anticancer. Bioactive compounds with anticancer mechanisms in plants can be controlled by specific genes. Therefore, it is important to elaborate on bioactive compounds and the genes involved. This article aims to discuss the genes encoding bioactive compounds in Indonesian medicinal plants and the mechanisms that can inhibit cancer cell growth. Several genes encode anticancer compounds, such as lectin-coding genes, the stigmasterol-coding CYP710A gene, the tocopherol-coding ?-TMT gene, the fatty acid-coding FAD gene, the doxorubicin-coding DXR gene, and the chalcone synthase-coding CHS gene. These genes have mechanisms to increase the expression of several apoptosis-promoting proteins, including BCL-2 family members, in several cancer cell models. This article also describes the potential utilization and creation of molecular markers linked to genes encoding anticancer chemicals and can be used as a reference for research on medicinal plants that is still limited. Knowledge of genes encoding anticancer compounds in plants can support future research in the development of cancer drugs.

Programming lipopeptide nanotherapeutics for tandem treatment of postsurgical infection and melanoma recurrence

Tumor recurrence and chronic bacterial infection constitute two major criteria in postsurgical intervention for malignant melanoma. One plausible strategy is the equipment of consolidation therapy after surgery, which relies on adjuvants to eliminate the residual tumor cells and inhibit bacterial growth. Until now, a number of proof-of-concept hybrid nanoadjuvants have been proposed to combat tumor recurrence and postsurgical bacterial infection, which may suffer from the potential bio-unsafety or involve complex design and synthesis. The batch-to-batch inconsistencies in drug composition further delay the clinical trials. To circumvent these issues, herein we develop a programmable strategy to generate lipopeptide nanotherapeutics with identical constitution for tandem intervention of postsurgical bacterial infection and cancer recurrence of melanoma. Increasing the number of hydrophobic linoleic acid within lipopeptides has been found to be a simple and practical strategy to improve the therapeutic outcomes for both tumor cells and bacteria. Self-assembled lipopeptide nanotherapeutics with two linoleic acid molecules possesses excellent antitumor activity and antimicrobial function toward both susceptible strains and drug-resistant bacteria. Arising from the incorporation of unsaturated linoleic acid, the unavoidable hemolysis of cationic peptide drugs was effectively alleviated. In vivo therapeutic abilities of postsurgical infection and tumor recurrence were investigated in BALB/c nude mice bearing a B16-F10 tumor model, with an incomplete surgical resection and in situ infection by methicillin-resistant Staphylococcus aureus (MRSA). Self-assembled lipopeptide nanotherapeutics could effectively inhibit cancer cell growth and bacterial infection, as well as promote wound healing. The easily scalable large-scale production, broad-spectrum antitumor and antibacterial bioactivities as well as fixed component endows lipopeptide nanotherapeutics as promising adjuvants for clinically postsurgical therapy of melanoma.

MicroRNA 29a therapy for CEACAM6-expressing lung adenocarcinoma

BackgroundNon-coding microRNAs (miRNAs) play critical roles in tumor progression and hold great promise as therapeutic agents for multiple cancers. MicroRNA 29a (miR-29a) is a tumor suppressor miRNA that inhibits cancer cell growth and tumor progression in non-small cell lung cancer. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which plays an important role in lung cancer progression, has been identified as a target of miR-29a. Here, we evaluated the therapeutic efficacy of a peptide vector capable of delivering miR-29a intracellularly using the acidic tumor microenvironment in a lung adenocarcinoma xenograft mouse model.MethodsA miRNA delivery vector was constructed by tethering the peptide nucleic acid form of miR-29a to a peptide with a low pH-induced transmembrane structure (pHLIP) to enable transport of the miRNAs across the plasma membrane. Tumor suppressive effects of pHLIP-miR29a on lung adenocarcinoma development in vivo were assessed using a BALB/c xenograft model injected with A549 cells.ResultsIncubation of A549 cells with pHLIP-miR-29a at an acidic pH downregulated endogenous CEACAM6 expression and reduced cell viability. Intravenous injection of the mice with pHLIP-miR-29a inhibited tumor growth by up to 18.1%. Intraperitoneal injection of cisplatin reduced tumor volume by 29.9%. Combined pHLIP-miR-29a + cisplatin treatment had an additive effect, reducing tumor volume up to 39.7%.ConclusionsDelivery of miR-29a to lung adenocarcinoma cells using a pHLIP-mediated method has therapeutic potential as a unique cancer treatment approach.

Effect of MoS2-PEG nanozymes on tumor cell multiplication

Molybdenum disulfide (MoS2), as a nanozyme, can effectively kill tumor cells by catalyzing H2O2 to produce extremely poisonous hydroxyl radical (*OH). In this work, spherical MoS2-PEG nanozymes were prepared by hydrothermal synthesis under the modification of polyethylene glycol (PEG). Firstly, XRD, XPS, SEM, TEM, and BET were used to analyze the phase, morphology, oxidation state, and distribution of each element of nanozyme. Secondly, the determination and verification of *OH as the main reactive oxygen species (ROS) in the MoS2-PEG nanozyme catalyzed Fenton reaction based on 3,3′,5,5′-tetramethyldiphenylamine (TMB) color reaction and electron spin resonance (ESR). Interestingly, MoS2-PEG nanozymes exhibited cytostatic rates of 43.9 % and 47.2 % in vitro in mouse breast cancer cell (4 T1) and mouse glioma cell (GL261) tumor cell models. In mouse fibroblast (L929) models, MoS2-PEG nanozymes showed excellent cytocompatibility and safety. Therefore, MoS2-PEG nanozyme may serve as an impactful drug to inhibit cancer cell growth.