Increasing evidence has shown that programmed cell death (PCD) plays a crucial role in tumorigenesis and cancer progression. The components of PCD are complex and include various mechanisms such as apoptosis, necroptosis, alkaliptosis, oxeiptosis, and anoikis, all of which are interrelated in their functions and regulatory pathways. Given the significance of these processes, it is essential to conduct a comprehensive study on PCD to elucidate its multifaceted nature. Key signaling pathways, particularly the caspase signaling pathway, the RIPK1/RIPK3/MLKL pathway, and the mTOR signaling pathway, are pivotal in regulating PCD and influencing tumor progression. In this review, we briefly describe the generation mechanisms of different PCD components and focus on the regulatory mechanisms of these three major signaling pathways within the context of global PCD. Furthermore, we discuss various tumor therapeutic compounds that target different signaling axes of these pathways, which may provide novel strategies for effective tumor therapy and help improve patient outcomes in cancer treatment.

Oral cancer is an aggressive malignancy with modest survival rates. It also causes disfigurement following surgical removal of the tumor, thus highlighting the need for new cancer treatment and tissue repair modalities. Carbon-based nanomaterials have emerged as promising tools in both anticancer and regenerative therapies.

We aimed to synthesize a new carbon-based nanomaterial (CBN) and test its antineoplastic effects, as well as its potential regenerative capacity.

A carbon nanomaterial, obtained by ball milling graphite flakes, was functionalized with polyvinylpyrrolidone (CBN/PVP). Its physicochemical properties were explored with X-ray diffraction (XRD), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), micro-Raman spectroscopy, fluorescent and scanning electron microscopy, and wettability analysis. For the antineoplastic effects investigation, oral cancer cells were treated with CBN/PVP and examined with MTT and migration assays, as well as cell-cycle and ROS production analyses. Gene expression was determined by qPCR. To examine the pro-regenerative capacity of CBN/PVP, dental pulp stem cell cultures (DPSCs) were treated with the nanomaterial and subjected to osteo- and chondro-induction.

Lower concentrations of CBN/PVP (50, 100 μg/mL) applied on cancer cells exerted remarkable cytotoxic effects, induced G1 cell-cycle arrest, and reduced cancer cell invasion potential by different mechanisms, including downregulation of the PI3K/AKT/mTOR pathway. In contrast, the addition of 50 µg/mL of CBN/PVP to DPSCs stimulated their survival and proliferation. CBN/PVP significantly enhanced both the osteogenic (p < 0.05) and chondrogenic (p < 0.01) induction of DPSCs.

The novel carbon-based nanomaterial displays unique characteristics, making it suitable in anticancer and regenerative therapies concomitantly.

Tuberculosis (TB) is a chronic wasting infectious disease caused by Mycobacterium tuberculosis (MTB) or Mycobacterium bovis that can be transmitted among people and domestic animals. During the development of TB, macrophages of the innate immune system can act against MTB via autophagy and apoptosis to prevent the spread of the disease. Among the many autophagy regulatory pathways, the adenosine monophosphate (AMP)-activated protein kinase (AMPK)-mammalian rapamycin target protein (mTOR)-Unc-51-like kinase 1 (ULK1) pathway has received considerable attention. This study investigates the regulatory role of the AMPK-mTOR-ULK1 pathway in attenuating M. bovis Bacillus Calmette-Guérin (BCG)-induced autophagy and apoptosis in murine monocyte macrophages (RAW264.7). Changes in macrophage autophagy and apoptosis were analyzed using the AMPK activator AICAR and inhibitor Compound C to interfere with the AMPK-mTOR-ULK1 pathway and siRNA to silence the pathway. Consequently, BCG stimulation of macrophages significantly activated the AMPK-mTOR-ULK1 pathway while BCG-induced macrophage AMPK activation promoted macrophage autophagy and apoptosis. Activation of the AMPK-mTOR-ULK1 pathway by AICAR significantly improved autophagy occurrence in BCG-induced macrophages and increased apoptosis while Compound C with siRNA produced opposing effects by attenuating autophagy and apoptosis in BCG-induced macrophages. Thus, the AMPK-mTOR-ULK1 pathway has a dual regulatory role in BCG-induced macrophage autophagy and apoptosis and may have synergistic effects. This study analyzes the mechanism of resistance of host cells to MTB and provides a theoretical basis for new therapeutic strategies and related drug development.

Natural polysaccharide-based nanoparticles are known for their non-toxic nature and diverse medical applications. Graphene oxide (GO) nanoparticles show potential in cancer treatment due to their ability to target medication delivery and influence ROS generation. These nanocomposites are versatile in gene transport, therapy, and photodynamic therapy, especially when surface-modified. Proper dispersion and functionalization of GO in polymer matrices are crucial, with examples like hyaluronic acid-functionalized GO offering versatile platforms for cancer drug administration. The potential of graphene oxide extends to cancer phototherapy, electronic nanowires, hydrogels, antibacterial nanocomposites, and environmental applications. When activated by polysaccharides, graphene-based nanocomposites exhibit anti-inflammatory and anticancer properties, making them valuable across various industries, including water treatment.

Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as a potential therapeutic target. Graphene oxide (GO), known for its oxygen-containing functional groups, biocompatibility, and potential for functionalization, holds promise in cancer treatment. However, its role in ferroptosis induction in CRC remains underexplored. The objective of this study was to investigate the effects of High Carbonyl Graphene Oxide (HC-GO) on ferroptosis in CRC and elucidate the underlying mechanisms.

In vitro assays were conducted to evaluate the impact of HC-GO on CRC cell proliferation, mitochondrial function, iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) production. The ferroptosis inhibitor Fer-1 was used to confirm the role of ferroptosis in HC-GO's anti-tumor effects. In vivo, the anti-tumor activity of HC-GO was assessed in a CRC xenograft model, with organ toxicity evaluated.

HC-GO significantly inhibited CRC cell proliferation, induced mitochondrial damage, and enhanced iron accumulation, lipid peroxidation, and ROS production. It also downregulated the ferroptosis-inhibiting proteins GPX4 and SLC7A11, which were reversed by Fer-1, confirming the involvement of ferroptosis in HC-GO's anti-cancer effects. In vivo, HC-GO significantly suppressed tumor growth without noticeable toxicity to vital organs.

HC-GO triggered ferroptosis in CRC cells by suppressing the System Xc-/GSH/GPX4 pathway, providing a novel therapeutic strategy for CRC treatment. These findings suggest HC-GO as a promising nanomedicine for clinical application, warranting further investigation to explore its potential in CRC therapy.

Nanoparticles, like graphene oxide (GO), are particles with unique physiochemical properties that enable their wide application in various areas of life. The effects of GO on individual cell organelles like mitochondria and the effects of interactions are worth investigating, as they can activate multiple cellular processes, such as autophagy or apoptosis. Mitochondrial injury plays an essential role in the majority of cell death routines. In the project, we investigated cell health status measured as mitochondrial inner membrane depolarization, autophagy, and apoptosis induction during long-term GO administration in food (0.02 μg g-1 and 0.2 μg g-1 of food). Two unique Acheta domesticus strains that differ in life strategy were used: wild-type and long-lived at three different life stages (larva, young adult, mature adult). The changes in mitochondrial trans-membrane potential were marked in the wild-type strain. The autophagy was lower in all GO-treated groups in both strains, and the apoptosis was lower in both strains in the mature adult crickets. Low GO concentrations treatment for the whole life, despite mitochondrial dysfunction, may lead to inhibition of autophagy and apoptosis by arresting the cell cycle for the duration of repair, and other repair tools are involved in the process of restoring homeostasis.

The balance of programmed cell death (PCD) mechanisms, including apoptosis, autophagy, necroptosis and others, is pivotal in cancer progression and treatment. Dysregulation of these pathways results in uncontrolled cell growth and resistance to conventional therapies. Nanomedicine offers a promising solution in oncology through targeted drug delivery enabling precise targeting of cancer cells while preserving healthy tissues. This approach reduces the side effects of traditional chemotherapy and enhances treatment efficacy by engaging PCD pathways. We details each PCD pathway, their mechanisms, and innovative nanomedicine strategies to activate these pathways, thereby enhancing therapeutic specificity and minimizing harm to healthy tissues. The precision of nanotechnology in targeting PCD pathways promises significant improvements in cancer treatment outcomes. This synergy between nanotechnology and targeted PCD activation could lead to more effective and less toxic cancer therapies, heralding a new era in cancer treatment.

Philadelphia-positive (Ph+) leukemia is a type of blood cancer also known as acute lymphoblastic leukemia (ALL), affecting 20-30% of adults diagnosed worldwide and having an engraved prognosis as compared to other types of leukemia. The current treatment regimens mainly rely on tyrosine kinase inhibitors (TKIs) and bone marrow transplants. To date, several generations of TKIs have been developed due to associated resistance and frequent relapse, with cardiovascular system anomalies being the most devastating complication. Nanotechnology has the potential to address these limitations by the targeted drug delivery and controlled release of TKIs. This study focused on the titanium dioxide (TiO2) and graphene oxide (GO) nanocomposite employment to load nilotinib and ponatinib TKIs for therapy of Ph+ leukemia cell line (K562) and Ba/F3 cells engineered to express BCR-ABL oncogene. Meanwhile, after treatment, the oncogene expressing fibroblast cells (Rat-1 P185) were evaluated for their colony formation ability under 3D conditions. To validate the nanocomposite formation, the TiO2-GO nanocomposites were characterized by scanning electron microscope, DLS, XRD, FTIR, zeta potential, EDX, and element mapping. The TKI-loaded TiO2-GO was not inferior to the free drugs after evaluating their effects by a cell viability assay (XTT), apoptosis induction, and colony formation inhibition. The cell signaling pathways of the mammalian target of rapamycin (mTOR), signal transducers and activators of transcription 5 (STAT5), and extracellular signal-regulated kinase (Erk1/2) were also investigated by Western blot. These signaling pathways were significantly downregulated in the TKI-loaded TiO2-GO-treated groups. Based on the findings above, we can conclude that TiO2-GO exhibited excellent drug delivery potential that can be used for Ph+ leukemia therapy in the future, subject to further investigations.

Cancer is the result of genetic abnormalities that cause normal cells to grow into neoplastic cells. Cancer is characterized by several distinct features, such as uncontrolled cell growth, extensive spreading to other parts of the body, and the ability to resist treatment. The scientists have stressed the development of nanostructures as novel therapeutic options in suppressing cancer, in response to the emergence of resistance to standard medicines. One of the specific mechanisms with dysregulation during cancer is autophagy. Nanomaterials have the ability to specifically carry medications and genes, and they can also enhance the responsiveness of tumor cells to standard therapy while promoting drug sensitivity. The primary mechanism in this process relies on autophagosomes and their fusion with lysosomes to break down the components of the cytoplasm. While autophagy was initially described as a form of cellular demise, it has been demonstrated to play a crucial role in controlling metastasis, proliferation, and treatment resistance in human malignancies. The pharmacokinetic profile of autophagy modulators is poor, despite their development for use in cancer therapy. Consequently, nanoparticles have been developed for the purpose of delivering medications and autophagy modulators selectively and specifically to the cancer process. Furthermore, several categories of nanoparticles have demonstrated the ability to regulate autophagy, which plays a crucial role in defining the biological characteristics and response to therapy of tumor cells.

Graphene and graphene-based materials have attracted growing interest for potential applications in medicine because of their good biocompatibility, cargo capability and possible surface functionalizations. In parallel, prototypic graphene-based devices have been developed to diagnose, imaging and track tumor growth in cancer patients. There is a growing number of reports on the use of graphene and its functionalized derivatives in the design of innovative drugs delivery systems, photothermal and photodynamic cancer therapy, and as a platform to combine multiple therapies. The aim of this review is to introduce the latest scientific achievements in the field of innovative composite graphene materials as potentially applied in cancer therapy. The "Technology and Innovation Roadmap" published in the Graphene Flagship indicates, that the first anti-cancer drugs using graphene and graphene-derived materials will have appeared on the market by 2030. However, it is necessary to broaden understanding of graphene-based material interactions with cellular metabolism and signaling at the functional level, as well as toxicity. The main aspects of further research should elucidate how treatment methods (e.g., photothermal therapy, photodynamic therapy, combination therapy) and the physicochemical properties of graphene materials influence their ability to modulate autophagy and kill cancer cells. Interestingly, recent scientific reports also prove that graphene nanocomposites modulate cancer cell death by inducing precise autophagy dysfunctions caused by lysosome damage. It turns out as well that developing photothermal oncological treatments, it should be taken into account that near-infrared-II radiation (1000-1500 nm) is a better option than NIR-I (750-1000 nm) because it can penetrate deeper into tissues due to less scattering at longer wavelengths radiation.

Osteosarcoma is a prevalent kind of primary bone malignancy. Trifluoperazine, as an antipsychotic drug, has anti-tumor activity against a variety of cancers. Nevertheless, the impact of trifluoperazine on osteosarcoma is unclear. Our investigation aimed to explore the mechanism of trifluoperazine's effect on osteosarcoma. We found that trifluoperazine inhibited 143B and U2-OS osteosarcoma cell proliferation in a method based on the dose. Furthermore, it was shown that trifluoperazine induced the accumulation of reactive oxygen species (ROS) to cause mitochondrial damage and induced mitophagy in osteosarcoma cells. Finally, combined with RNA-seq results, we first demonstrated the AMPK/mTOR/ULK1 signaling pathway as a potential mechanism of trifluoperazine-mediated mitophagy in osteosarcoma cells and can be suppressed by AMPK inhibitor Compound C.

Graphene oxide (GO) has received increasing attention in the life sciences because of its potential for various applications. Although GO is generally considered biocompatible, it can negatively impact cell physiology under some circumstances. Here, we demonstrate that the cytotoxicity of GO greatly varies depending on the cell adhesion states. Human HCT-116 cells in a non-adhered state were more susceptible to GO than those in an adherent state. Apoptosis was partially induced by GO in both adhered and non-adhered cells to a similar extent, suggesting that apoptosis induction does not account for the selective effects of GO on non-adhered cells. GO treatment rapidly decreased intracellular ATP levels in non-adhered cells but not in adhered ones, suggesting ATP depletion as the primary cause of GO-induced cell death. Concurrently, autophagy induction, a cellular response for energy homeostasis, was more evident in non-adhered cells than in adhered cells. Collectively, our observations provide novel insights into GO's action with regard to cell adhesion states. Because the elimination of non-adhered cells is important in preventing cancer metastasis, the selective detrimental effects of GO on non-adhered cells suggest its therapeutic potential for use in cancer metastasis.

Nanoparticles have unique physical and chemical properties and are currently widely used in disease diagnosis, drug delivery, and new drug development in biomedicine. In recent years, the role of nanomedical technology in cancer treatment has become increasingly obvious. Autophagy is a multi-step degradation process in cells and an important pathway for material and energy recovery. It is closely related to the occurrence and development of cancer. Because nanomaterials are highly targeted and biosafe, they can be used as carriers to deliver autophagy regulators; in addition to their favorable physicochemical properties, nanomaterials can be employed to carry autophagy inhibitors, reducing the breakdown of chemotherapy drugs by cancer cells and thereby enhancing the drug's efficacy. Furthermore, certain nanomaterials can induce autophagy, triggering oxidative stress-mediated autophagy enhancement and cell apoptosis, thus constraining the progression of cancer cells.There are various types of nanoparticles, including liposomes, micelles, polymers, metal-based materials, and carbon-based materials. The majority of clinically applicable drugs are liposomes, though other materials are currently undergoing continuous optimization. This review begins with the roles of autophagy in tumor treatment, and then focuses on the application of nanomaterials with autophagy-regulating functions in tumor treatment.

Autophagy is a lysosomal self-degradation pathway that plays an important protective role in maintaining intracellular environment. Deregulation of autophagy is related to several diseases, including cancer, infection, neurodegeneration, aging, and heart disease. In this review, we will summarize recent advances in autophagy-mediated nanomaterials for tumor therapy. Firstly, the autophagy signaling pathway for tumor therapy will be reviewed, including oxidative stress, mammalian target of rapamycin (mTOR) signaling and autophagy-associated genes pathway. Based on that, many autophagy-mediated nanomaterials have been developed and applied in tumor therapy. According to the different structure of nanomaterials, we will review and evaluate these autophagy-mediated nanomaterials' therapeutic efficacy and potential clinical application.

The latest advancements in oncology involves the creation of multifunctional nanostructures. The integration of nanoparticles into the realm of cancer therapy has brought about a transformative shift, revolutionizing the approach to addressing existing challenges and limitations in tumor elimination. This is particularly crucial in combating the emergence of resistance, which has significantly undermined the effectiveness of treatments like chemotherapy and radiotherapy. GO stands as a carbon-derived nanoparticle that is increasingly finding utility across diverse domains, notably in the realm of biomedicine. The utilization of GO nanostructures holds promise in the arena of oncology, enabling precise transportation of drugs and genetic material to targeted sites. GO nanomaterials offer the opportunity to enhance the pharmacokinetic behavior and bioavailability of drugs, with documented instances of these nanocarriers elevating drug accumulation at the tumor location. The GO nanostructures encapsulate genes, shielding them from degradation and facilitating their uptake within cancer cells, thereby promoting efficient gene silencing. The capability of GO to facilitate phototherapy has led to notable advancements in reducing tumor progression. By PDT and PTT combination, GO nanomaterials hold the capacity to diminish tumorigenesis. GO nanomaterials have the potential to trigger both cellular and innate immunity, making them promising contenders for vaccine development. Additionally, types of GO nanoparticles that respond to specific stimuli have been applied in cancer eradication, as well as for the purpose of cancer detection and biomarker diagnosis. Endocytosis serves as the mechanism through which GO nanomaterials are internalized. Given these advantages, the utilization of GO nanomaterials for tumor elimination comes highly recommended.

The application of biomaterials on immune regenerative strategies to deal with unsolved pathologies is getting attention in the field of tissue engineering. In this context, graphene oxide (GO) has been proposed as an immune-mimetic material largely used for developing stem cell-based regenerative therapies, since it has shown to influence stem cell behavior and modulate their immune response. Similarly, amniotic epithelial stem cells (AECs) are getting an increasing clinical interest as source of stem cells due to their great plasticity and immunomodulatory paracrine activities, even though GO bio-mimetic effects still remain unknown. To this aim, GO-functionalized glass coverslips have been used for AECs culture. The results demonstrated how GO-coating is able to induce and accelerate the Epithelial-Mesenchymal Transition (EMT), in a process mediated by the intracellular activation of TGFβ1-SMAD2/3 signaling pathway. The trans-differentiation towards mesenchymal phenotype provides AECs of migratory ability and substantially changes the pattern of cytokines secretion upon inflammatory stimulus. Indeed, GO-exposed AECs enhance their pro-inflammatory interleukins production thus inducing a more efficient activation of macrophages and, at the same time, by slightly reducing their inhibitory action on peripheral blood mononuclear cells proliferation. Therefore, the adhesion of AECs on GO-functionalized surfaces might contribute to the generation of a tailored microenvironment useful to face both the phases of the inflammation, thereby fostering the regenerative process.

One of the components of bee venom is melittin (M), which has strong lysing properties on membranes. M has high toxicity to cancer cells, but it also affects healthy cells, making it necessary to use methods for targeted delivery to ensure treatment. This research is a continuation of previous studies using graphene nanomaterials as M carriers to breast cancer cells. The studies described below are conducted on a more organized biological structure than what is found in vitro cells, namely, cancerous tumors grown on a chicken embryo chorioallantoic membrane. Caspase 3 and 8 levels are analyzed, and the level of oxidative stress markers and changes in protein expression for cytokines are examined. The results show that M complexes with nanomaterials reduce the level of oxidative stress more than M alone does, but the use of graphene (GN) as a carrier increases the level of DNA damage to a greater extent than the increase caused by M alone. An analysis of cytokine levels shows that the use of the M and GN complex increases the level of proteins responsible for inhibiting tumor progression to a greater extent than the increase occasioned by a complex with graphene oxide (GO). The results suggest that the use of GN as an M carrier may increase the toxic effect of M on structures located inside a cell.

Nanotechnology is a growing field, with many potential biomedical applications of nanomedicine for the treatment of different diseases, particularly cancer, on the horizon. Graphene oxide (GO) nanoparticles can act as carbon-based nanocarriers with advantages such as a large surface area, good mechanical strength, and the capacity for surface modification. These nanostructures have been extensively used in cancer therapy for drug and gene delivery, photothermal therapy, overcoming chemotherapy resistance, and for imaging procedures. In the current review, we focus on the biological functions of GO nanoparticles as regulators of apoptosis and autophagy, the two major forms of programmed cell death. GO nanoparticles can either induce or inhibit autophagy in cancer cells, depending on the conditions. By stimulating autophagy, GO nanocarriers can promote the sensitivity of cancer cells to chemotherapy. However, by impairing autophagy flux, GO nanoparticles can reduce cell survival and enhance inflammation. Similarly, GO nanomaterials can increase ROS production and induce DNA damage, thereby sensitizing cancer cells to apoptosis. In vitro and in vivo experiments have investigated whether GO nanomaterials show any toxicity in major body organs, such as the brain, liver, spleen, and heart. Molecular pathways, such as ATG, MAPK, JNK, and Akt, can be regulated by GO nanomaterials, leading to effects on autophagy and apoptosis. These topics are discussed in this review to shed some lights towards the biomedical potential of GO nanoparticles and their biocompatibility, paving the way for their future application in clinical trials.