Targeting GLI1 and BAX by nanonoscapine could impede prostate adenocarcinoma progression.

Prostate cancer as a critical global health issue, requires the exploration of a novel therapeutic approach. Noscapine, an opium-derived phthalide isoquinoline alkaloid, has shown promise in cancer treatment thanks to its anti-tumorigenic properties. However, limitations such as low bioavailability and potential side effects have hindered its clinical application. This study introduces nanonoscapine as a novel medication to overcome these challenges, leveraging the advantages of improved drug delivery and efficacy achieved in nanotechnology. We monitored the effects of nanonoscapine on the androgen-sensitive human prostate adenocarcinoma cell line, LNCaP, investigating its impact on GLI1 and BAX genes' expressions, crucial regulators of cell cycle and apoptosis. Our findings, from MTT assays, flow cytometry, and gene expression analyses, have demonstrated that nanonoscapine effectively inhibits prostate cancer cell proliferation by inducing G2/M phase arrest and apoptosis. Furthermore, through bioinformatics and computational analyses, we have revealed the underlying molecular mechanisms, underscoring the therapeutic potential of nanonoscapine in enhancing patient outcomes. This study highlights the significance of nanonoscapine as an alternative or adjunct treatment to conventional chemotherapy, warranting further investigation in clinical settings.

Novel Bovine Serum Albumin-Decorated-Nanostructured Lipid Carriers Able to Modulate Apoptosis and Cell-Cycle Response in Ovarian, Breast, and Colon Tumoral Cells.

A novel nanoscale approach was developed for the improved cellular internalization of hybrid bovine serum albumin-lipid nanocarriers loaded with piperine (NLC-Pip-BSA) in different tumor cells. The effect of the BSA-targeted-NLC-Pip and untargeted-NLC-Pip on the viability, proliferation, and levels of cell-cycle damage and apoptosis in the colon (LoVo), ovarian (SKOV3) and breast (MCF7) adenocarcinoma cell lines was comparatively discussed. NLCs were characterized concerning particle size, morphology, zeta potential, phytochemical encapsulation efficiency, ATR-FTIR, and fluorescence spectroscopy. The results showed that NLC-Pip-BSA showed a mean size below 140 nm, a zeta potential of -60 mV, and an entrapment efficiency of 81.94% for NLC-Pip and 80.45% for NLC-Pip-BSA. Fluorescence spectroscopy confirmed the coating of the NLC with the albumin. By MTS and RTCA assays, NLC-Pip-BSA showed a more pronounced response against the LoVo colon cell line and MCF-7 breast tumor cell lines than against the ovarian SKOV-3 cell line. Flow cytometry assay demonstrated that the targeted NLC-Pip had more cytotoxicity and improved apoptosis than the untargeted ones in MCF-7 tumor cells (p < 0.05). NLC-Pip caused a significant increase in MCF-7 breast tumor cell apoptosis of ~8X, while NLC-Pip-BSA has shown an 11-fold increase in apoptosis.

Biomaterial-assisted tumor therapy: A brief review of hydroxyapatite nanoparticles and its composites used in bone tumors therapy.

Malignant bone tumors can inflict significant damage to affected bones, leaving patients to contend with issues like residual tumor cells, bone defects, and bacterial infections post-surgery. However, hydroxyapatite nanoparticles (nHAp), the principal inorganic constituent of natural bone, possess numerous advantages such as high biocompatibility, bone conduction ability, and a large surface area. Moreover, nHAp's nanoscale particle size enables it to impede the growth of various tumor cells via diverse pathways. This article presents a comprehensive review of relevant literature spanning the past 2 decades concerning nHAp and bone tumors. The primary goal is to explore the mechanisms responsible for nHAp's ability to hinder tumor initiation and progression, as well as to investigate the potential of integrating other drugs and components for bone tumor diagnosis and treatment. Lastly, the article discusses future prospects for the development of hydroxyapatite materials as a promising modality for tumor therapy.

Precise Control of Glioma Cell Apoptosis Induced by Micro-Plasma-Activated Water (µ-PAW).

To verify the existence of plasma with the potential to kill tumor cells, this paper designed a novel helium (He) micro-plasma jet array device and detected the concentration of typical long-lived reactive oxygen and nitrogen species (RONS) with oxidative activity generated by it. The paper described a new He micro-plasma jet array device consisting of nine flexible quartz capillaries with an inner diameter of 75 µm arranged in a 3 × 3 array. Sterilized ultrapure water (up water) was first treated with the He micro-plasma jet array device to activate it to form enriched RONS micro-plasma-activated water (µ-PAW), and then µ-PAW was added to the cell culture medium (with cells) to observe the proliferation of human glioma cells. The concentration of long-lived RONS, such as nitrate (NO3-), was detected according to Beer-Lambert's law in combination with UV spectrophotometry as well as a color development method. The MTT Cell Proliferation and Cytotoxicity Assay Kit combined with the Hoechst Staining Kit were used to assess the proliferation status of the cells. The results showed that the range of RONS concentration variation could be controlled in the order of micromoles (µmol), while plasma-induced tumor cell death is apoptosis that does not affect the surrounding environment.

Efficient Immunotherapy of Drug-Free Layered Double Hydroxide Nanoparticles via Neutralizing Excess Acid and Blocking Tumor Cell Autophagy.

Cancer immunotherapy efficacy is largely limited by the suppressive tumor immune microenvironment (TIME) where antitumor immune cells are inhibited and tumor antigens continue to mutate or be lost. To remodel the TIME, we here applied weakly alkaline layered double hydroxide nanoparticles (LDH NPs) to neutralize the excess acid and block autophagy of tumor cells for neoadjuvant cancer immunotherapy. Peritumoral injection of LDH NPs provided a long-term and efficient acid-neutralization in the TIME, blocked the lysosome-mediated autophagy pathway in tumor cells, and increased the levels of antitumor tumor-associated macrophages and T cells. These LDH NPs captured tumor antigens released in the tumor tissues and effectively inhibited the growth of both melanoma and colon tumors in vivo. These findings indicate that LDH NPs, as an immunomodulator and adjuvant, successfully "awaken" and promote the host innate and adaptive immune systems, showing promising potential for solid tumor immunotherapy.

The Role of miRNA in Tumor Immune Escape and miRNA-Based Therapeutic Strategies.

Tumor immune escape is a critical step in the malignant progression of tumors and one of the major barriers to immunotherapy, making immunotherapy the most promising therapeutic approach against tumors today. Tumor cells evade immune surveillance by altering the structure of their own, or by causing abnormal gene and protein expression, allowing for unrestricted development and invasion. These genetic or epigenetic changes have been linked to microRNAs (miRNAs), which are important determinants of post-transcriptional regulation. Tumor cells perform tumor immune escape by abnormally expressing related miRNAs, which reduce the killing effect of immune cells, disrupt the immune response, and disrupt apoptotic pathways. Consequently, there is a strong trend toward thoroughly investigating the role of miRNAs in tumor immune escape and utilizing them in tumor treatment. However, because of the properties of miRNAs, there is an urgent need for a safe, targeted and easily crossed biofilm vehicle to protect and deliver them in vivo, and exosomes, with their excellent biological properties, have successfully beaten traditional vehicles to provide strong support for miRNA therapy. This review summarizes the multiple roles of miRNAs in tumor immune escape and discusses their potential applications as an anti-tumor therapy. Also, this work proposes exosomes as a new opportunity for miRNA therapy, to provide novel ideas for the development of more effective tumor-fighting therapeutic approaches based on miRNAs.

Inducing Tumor Cell Apoptosis: Mediated Survivin miRNA by Ultrasound and Cationic Lipid Contrast Agent.

BACKGROUND: Non-viral delivery systems is a promising method for gene or drug delivery. Polyethyleneimine (PEI) is a double-edged sword. It internalizes itself into the cell through endocytosis and promotes gene transfer efficiency. However, the strong positive charge also makes PEI highly toxic to cells. Ultrasound-targeted microbubble destruction (UTMD) is a promising non-viral method for gene and drug delivery, but its efficiency still needs to be improved. OBJECTIVE: The aim of this study was to explore a system that combines ultrasound with non-viral gene delivery for the treatment of cervical cancer HeLa cells. METHODS: In this study, we synthesized a kind of cationic ultrasound contrast agent(CUCA) that the physical and chemical properties, gene carrying capacity and cytotoxicity were verified. On the basis of previous studies, we further optimized the following transfusion parameters including ultrasound parameters, microbubble concentration, plasmid concentration, cell density and other parameters. The experiment was designed to compare the following six groups: (1) Plasmid group (P group), plasmid 15 µg; (2) PEI + plasmid group (PEI + P group),1 µl of PEI containing 10 nmol nitrogen and 1 µg of DNA containing 3 nmol phosphate for a PEI/DNA ratio equal to a nitrogen/phosphate ratio of 7 for transfection; (3) Ultrasound + plasmid group (US + P), plasmid 15 µg; (4) Ultrasound + cationic liposomal ultrasound contrast agent + plasmid group (UTMD + P group), plasmid 15 µg and cationic liposomal ultrasound contrast agent 5%; (5) Ultrasound + cationic liposomal ultrasound contrast agent + PEI + plasmid group (UTMD + PEI + P group), PEI/DNA ratio equal to a nitrogen/phosphate ratio of 7 for transfection and cationic liposomal ultrasound contrast agent 5%; and (6) Blank group, no treatment), The influence on Hela cells was observed under microscope, the efficiency of apoptosis was measured by flow cytometry, and cell viability was tested in CCK 8. RESULTS: The optimized transfection parameters can improve the transfection efficiency of ultrasound combined with C-UCA to a certain extent, but its transfection efficiency is still lower than that of branched polyethyleneimine (bPEI) 25 kDa. By investigating the effect of HeLa cells apoptosis induced by UTMD in combination with PEI mediated survivin miRNA, we found that both PEI alone and ultrasound in combination with CUCA were able to transfect cells with survivin miRNA to effectively induce HeLa cell apoptosis. However, the synergistic effect between the two methods was not significant. CONCLUSION: In contrast, the combined use of ultrasound, C-UCA and PEI may significantly reduce the transfection efficiency of UTMD and PEI, and the specific mechanism remains to be further studied.

[Preparation of curcumin TPP-PEG-PE nanomicelles with mitochondrial targeting and lysosomal escape functions and its effect on promoting breast cancer cell apoptosis].

Orthogonal experiments were used to optimize the process parameters of curcumin TPP-PEG-PCL nanomicelles; the particle size, electric potential and morphology under the electron microscope were systematically detected for the curcumin TPP-PEG-PCL nanomicelles; and the stability and in vitro release of the curcumin TPP-PEG-PCL nanomicelles were investigated. With DID fluorescent dye as the fluorescent probe, flow cytometry was used to study the uptake of nanomicelles by breast cancer cells, and laser confocal microscopy was used to study the mitochondrial targeting and lysosomal escape functions of nanomicelles. Under the same dosage conditions, the effect of curcumin TPP-PEG-PCL nanomicelles on promoting the apoptosis of breast cancer cells was evaluated. The optimal particle size of curcumin TPP-PEG-PCL nanomicelle was(17.3±0.3) nm, and the Zeta potential was(14.6±2.6) mV in orthogonal test. Under such conditions, the micelle appeared as regular spheres under the transmission electron microscope. Fluorescence test results showed that TPP-PEG-PCL nanomicelles can promote drug uptake by tumor cells, escape from lysosomal phagocytosis, and target the mitochondria. The cell survival rate and Hoechst staining positive test results showed that curcumin TPP-PEG-PCL nanomicelles had a good effect on promoting apoptosis of breast cancer cells. The curcumin TPP-PEG-PCL micelles can significantly reduce the mitochondrial membrane potential of breast cancer cells, increase the release of cytochrome C, significantly increase the expression of pro-apoptotic protein Bcl-2 and reduce the expression of anti-apoptotic Bax protein. These test results were significantly better than those of curcumin PEG-PCL nanomicelles and curcumin, with statistically significant differences. The results revealed that curcumin TPP-PEG-PCL nanomicelles can well target breast cancer cell mitochondria and escape from the lysosomal capture, thereby enhancing the drug's role in promoting tumor cell apoptosis.

LC3-Associated Phagocytosis (LAP): A Potentially Influential Mediator of Efferocytosis-Related Tumor Progression and Aggressiveness.

One aim of cancer therapies is to induce apoptosis of tumor cells. Efficient removal of the apoptotic cells requires coordinated efforts between the processes of efferocytosis and LC3-associated phagocytosis (LAP). However, this activity has also been shown to produce anti-inflammatory and immunosuppressive signals that can be utilized by live tumor cells to evade immune defense mechanisms, resulting in tumor progression and aggressiveness. In the absence of LAP, mice exhibit suppressed tumor growth during efferocytosis, while LAP-sufficient mice show enhanced tumor progression. Little is known about how LAP or its regulators directly affect efferocytosis, tumor growth and treatment responses, and identifying the mechanisms involved has the potential to lead to the discovery of novel approaches to target cancer cells. Also incompletely understood is the direct effect of apoptotic cancer cells on LAP. This is particularly important as induction of apoptosis by current cytotoxic cancer therapies can potentially stimulate LAP following efferocytosis. Herein, we highlight the current understanding of the role of LAP and its relationship with efferocytosis in the tumor microenvironment with a view to presenting novel therapeutic strategies.

Preparation of curcumin TPP-PEG-PE nanomicelles with mitochondrial targeting and lysosomal escape functions and its effect on promoting breast cancer cell apoptosis / 中国中药杂志

Orthogonal experiments were used to optimize the process parameters of curcumin TPP-PEG-PCL nanomicelles; the particle size, electric potential and morphology under the electron microscope were systematically detected for the curcumin TPP-PEG-PCL nanomicelles; and the stability and in vitro release of the curcumin TPP-PEG-PCL nanomicelles were investigated. With DID fluorescent dye as the fluorescent probe, flow cytometry was used to study the uptake of nanomicelles by breast cancer cells, and laser confocal microscopy was used to study the mitochondrial targeting and lysosomal escape functions of nanomicelles. Under the same dosage conditions, the effect of curcumin TPP-PEG-PCL nanomicelles on promoting the apoptosis of breast cancer cells was evaluated. The optimal particle size of curcumin TPP-PEG-PCL nanomicelle was(17.3±0.3) nm, and the Zeta potential was(14.6±2.6) mV in orthogonal test. Under such conditions, the micelle appeared as regular spheres under the transmission electron microscope. Fluorescence test results showed that TPP-PEG-PCL nanomicelles can promote drug uptake by tumor cells, escape from lysosomal phagocytosis, and target the mitochondria. The cell survival rate and Hoechst staining positive test results showed that curcumin TPP-PEG-PCL nanomicelles had a good effect on promoting apoptosis of breast cancer cells. The curcumin TPP-PEG-PCL micelles can significantly reduce the mitochondrial membrane potential of breast cancer cells, increase the release of cytochrome C, significantly increase the expression of pro-apoptotic protein Bcl-2 and reduce the expression of anti-apoptotic Bax protein. These test results were significantly better than those of curcumin PEG-PCL nanomicelles and curcumin, with statistically significant differences. The results revealed that curcumin TPP-PEG-PCL nanomicelles can well target breast cancer cell mitochondria and escape from the lysosomal capture, thereby enhancing the drug's role in promoting tumor cell apoptosis.

siRNA-based Analysis of the Abrogation of the Protective Function of Membrane-associated Catalase of Tumor Cells.

Tumor cells, in contrast to non-malignant cells, show sustained expression of membrane-associated NADPH oxidase-1 and therefore generate extracellular superoxide anions and their dismutation product H2O2 In order to prevent intercellular reactive oxygen species/reactive nitrogen species (ROS/RNS)-dependent apoptosis-inducing signaling, tumor cells need to express membrane-associated catalase that interferes with HOCl and nitric oxide/peroxynitrite signaling. Catalase is attached to tumor cells through the activity of transglutaminase-2 and is prevented from superoxide anion-dependent inhibition through coexpression of membrane-associated superoxide dismutase. Therefore, specific inhibition of membrane-associated catalase should reactivate intercellular ROS/RNS-dependent apoptosis-inducing signaling. These processes are analyzed here through small interfering RNA-mediated knockdown of essential signaling compounds. This allows to establish a rather comprehensive picture of intercellular ROS/RNS signaling that may be instrumental for future therapeutic approaches.

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells.

Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cells to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death.

Staphylococcal entertotoxins of the enterotoxin gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells.

The egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitrous oxide (NO) and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11-25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200-250 µM), a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA) (0.3 mM), an NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies, respectively, and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma > osteogenic sarcoma > melanoma > breast carcinoma >neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells.

Expression of the PXR gene in various types of cancer and drug resistance.

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. PXR is a key xenobiotic receptor that regulates the expression of genes implicated in drug metabolism, detoxification and clearance, including drug metabolizing enzymes and transporters, suggesting that it is significant in the drug resistance of cancer cells. PXR is expressed in a wide range of tissues in the human body. Studies have demonstrated that PXR is expressed in a variety of tumor types, correlating not only with drug resistance but also with the cell proliferation, apoptosis and prognosis of cancer. The purpose of the present review is to provide a comprehensive review of PXR and its potential roles in multidrug resistance and the biological characteristics of PXR-positive tumors.

A Preliminary Study on the Role of Mitochondrial Protein, Bcl-2 and Bax in Tumorigenesis / 中国肿瘤临床

Objective: To study the expressions of mitochondrial protein (MAB1273), Bcl-2, and Bax in renal cell carcinoma and to investigate their role in the tumorigenesis. Methods: The expressions of mitochondrial protein, Bcl-2 and Bax were detected by immunohistochemistry SP method in 9 tissue samples of renal on-cocytoma, 6 samples of chromophobe carcinoma, 23 samples of clear cell carcinoma and 12 samples of normal renal tissue. Results: The expression of MAB1273 in renal oncocytoma, chromophobe carcinoma and clear cell carcinoma was much higher than that in normal renal tissue (P=0.006). No significant difference was found in MAB1273 expression among the three types of renal carcinoma. The expression of Bcl-2 was higher in the renal carcinoma groups than in the normal renal tissue group, with a significant difference (P=0.008). The expression of Bax was not different among all of the groups (P=0.057). Rank correlation analysis showed a positive correlation between MAB1273 and Bcl-2 expression (r=0.341, P=0.015). The expression of Bcl-2 was negatively correlated with Bax expression (r= -0.287, P=0.043). Conclusion: Overexpression of mitochondrial protein and Bcl-2 and underexpression of Bax may play a part in the genesis of renal oncocytoma, chromophobe carcinoma and the clear cell carcinoma, indicating that overexpression of MAB1273 may be correlated with apoptosis of renal cell carcinoma cells.