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Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing spe...
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Autophagy and the lysosomal system, together referred to as the autophagolysosomal system, is a cellular quality control network which maintains cellular health and homeostasis by removing cellular waste including protein aggregates, damaged organelles, and invading pathogens. As such, the autophagolysosomal system has roles in a variety of pathoph...
Citations
... Indeed, autophagy is a process that intervenes in the regeneration of cellular components and whose dysregulation is associated with certain pathologies, such as tumors. For this reason, modulation of autophagy, which can be both cytoprotective and cytotoxic, is a promising therapeutic approach in tumor therapy [96]. In a clinical study begun in 2021, the corcin displayed an effect on cardiovascular dysfunction caused by breast tumor treatment. ...
Plants and plant extracts have long been acknowledged as valuable resources for the development of therapeutic formulations for various diseases. Among them, numerous plants and plant-derived products have demonstrated cytotoxic and/or anti-tumor properties. Saffron, particularly due to its major compounds, namely crocin, crocetin, and safranal, stands out as a promising candidate in this regard. Our research undertakes a literature review, reaffirming the antioxidant, anti-inflammatory, and, notably, anti-tumor properties of saffron and its major constituents. Additionally, this study examines relevant patent documents, highlighting innovative applications for saffron and its major compounds in cancer therapy. The review discusses the progress in purifying the compounds extracted from saffron and assesses their impact on cytotoxic trial outcomes, the potential synergies between certain saffron compounds and established cytotoxic molecules, and the limitations of the patents examined, particularly concerning reported clinical evidence. Researchers who focus on advances in oncology will know from our findings the evolution of the patent landscape regarding cytotoxic and/or anti-tumor therapeutic applications using saffron or its main compounds. Moreover, investigators can draw inspiration from patents leveraging traditional knowledge, particularly from Chinese medicine, to clarify specific active molecules and their mechanisms of action and can expedite the translation of these findings into clinically relevant interventions, potentially enhancing cancer therapy outcomes.
... according to the recommendations of the Nomenclature committee on cell Death (NcDD) besides apoptosis, other types of cell death have been distinguished including autophagy 71 . Nowadays, the role of autophagy in development of cancer is not clear 72 . to evaluate whether the mechanism of action of novel pyrazolo[4,3-e]tetrazolo [1,5-b] [1,2,4]triazine on the breast cancer cells is related to autophagic response, we measured the number of autophagosomes and level of beclin-1 after 24 h incubation with compound 3b. ...
... the role of autophagy in cancer is still inconclusive. however, many scientific reports indicate that autophagy is a basis for anticancer activity 25,27,72,73 . One of the factors involved in either apoptosis or autophagy is mtOR. ...
In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.
... Inhibition of protective autophagy can make GBM cells more sensitive to chemotherapeutic or radiotherapeutic agents, but excessive autophagic activation in GBM cells can also induce autophagic cell death [14]. Diverse autophagy modulators, such as CQ, HCQ, and Lys05, have been evaluated for their anti-GBM efficacy [15]. ...
Background
Glioblastoma (GBM) is the most common brain tumor with the worst prognosis. Temozolomide is the only first-line drug for GBM. Unfortunately, the resistance issue is a classic problem. Therefore, it is essential to develop new drugs to treat GBM. As an oncogene, Skp2 is involved in the pathogenesis of various cancers including GBM. In this study, we investigated the anticancer effect of AAA237 on human glioblastoma cells and its underlying mechanism.
Methods
CCK-8 assay was conducted to evaluate IC50 values of AAA237 at 48, and 72 h, respectively. The Cellular Thermal Shift Assay (CETSA) was employed to ascertain the status of Skp2 as an intrinsic target of AAA237 inside the cellular milieu. The EdU-DNA synthesis test, Soft-Agar assay and Matrigel assay were performed to check the suppressive effects of AAA237 on cell growth. To identify the migration and invasion ability of GBM cells, transwell assay was conducted. RT-qPCR and Western Blot were employed to verify the level of BNIP3. The mRFP-GFP-LC3 indicator system was utilized to assess alterations in autophagy flux and investigate the impact of AAA237 on the dynamic fusion process between autophagosomes and lysosomes. To investigate the effect of compound AAA237 on tumor growth in vivo, LN229 cells were injected into the brains of mice in an orthotopic model.
Results
AAA237 could inhibit the growth of GBM cells in vitro. AAA237 could bind to Skp2 and inhibit Skp2 expression and the degradation of p21 and p27. In a dose-dependent manner, AAA237 demonstrated the ability to inhibit colony formation, migration, and invasion of GBM cells. AAA237 treatment could upregulate BNIP3 as the hub gene and therefore induce BNIP3-dependent autophagy through the mTOR pathway whereas 3-MA can somewhat reverse this process. In vivo, the administration of AAA237 effectively suppressed the development of glioma tumors with no side effects.
Conclusion
Compound AAA237, a novel Skp2 inhibitor, inhibited colony formation, migration and invasion of GBM cells in a dose-dependent manner and time-dependent manner through upregulating BNIP3 as the hub gene and induced BNIP3-dependent autophagy through the mTOR pathway therefore it might be a viable therapeutic drug for the management of GBM.
Graphical Abstract
... Modulators that are presently being tested in cancer either in the late stage of preclinical studies or at different stages of clinical trials: Biricodar, Dofequidar, Elacridar, Laniquidar, Tariquidar, Valspodar, and Zosuquidar [42][43][44][45][46]. Modulators known to reduce MDR in tumor cells may be tested for their potency in Candida as a potent antifungal or MDRmodifying agent. ...
The escalating prevalence of membrane drug transporters and drug efflux pumps in pathogenic yeast like Candida albicans necessitates a comprehensive understanding of their roles in MDR. The overexpression of drug transporter families, ABC and MFS, implicated in MDR through drug efflux and poses a significant challenge in the diagnosis and treatment of fungal infection. Various mechanisms have been proposed for MDR; however, the upregulation of ABC and MFS superfamily transporters is most noticeable in MDR. The direct inhibition of these transporters seems an efficient strategy to overcome this problem. The goal of the article is to present an overview of the prospect of utilizing these modulators of C. albicans drug transports as effective antifungal molecules against MDR addressing a critical gap in the field. The review tries to address to prevent drug extrusion by modulating the expression of drug transporters of C. albicans. The review discussed the progress in identifying potent, selective, and non-toxic modulators of these transporters to develop some effective antifungals and overcome MDR. We reviewed major studies in this area and found that recent work has shifted toward the exploration of natural compounds as potential modulators to restore drug sensitivity in MDR fungal cells. The focus of this review is to survey and interpret current research information on modulators of C. albicans drug transporters from natural sources emphasizing those compounds that are potent antifungal agents.
... Autophagy is a dichotomous process that may cause tumor growth or inhibit it. This evidence suggests that autophagy plays a complicated role in cancer [43]. Therefore, an excessive decrease and increase in autophagy can induce the anticancer activity of medicinal plants. ...
... Therefore, an excessive decrease and increase in autophagy can induce the anticancer activity of medicinal plants. There is a relationship between apoptosis and autophagy on the level of the molecular regulation of the apoptosis pathways such as Bcl-2/Beclin 1, p53, p62, caspases, and autophagyrelated (ATG) proteins [43]. However, autophagy may induce cell death independently of necrosis or apoptosis [44]. ...
Background
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide.
Objective
Considering the side effects of chemotherapy treatments, we reviewed the anti-cancer effects and mechanisms of bromelain on colon cancer cells in this study.
Methods
The PRISMA guidelines were followed in the design of this systematic review. Various databases, including PubMed, Web of Science, Cochrane Library, and Scopus, were thoroughly searched. Finally, 14 articles were retrieved after considering the study's inclusion and exclusion criteria. The desired data were extracted, entered into an Excel file, and the study results were reviewed.
Results
According to the included studies, bromelain can significantly reduce the survival and death of cloned cancer cells through different mechanisms. These mechanisms include impeding tumor growth and metastasis by reducing mucins production/secretion and increasing/reducing reactive oxygen species (ROS) production. Moreover, bromelain induces apoptosis via reduced expression of Bcl-2, extracellular signal-related kinase (ERK), Akt, activation caspase system (caspase-3, 7, 8, and 9), and extranuclear p53. Ferroptosis was another mechanism of causing cell death. In addition, bromelain activates the autophagy pathway, lysosome formation, and deregulation of other autophagyrelated proteins.
Conclusion
Bromelain effectively inhibits colon cancer cells' growth, proliferation, and metastasis and reduces their survival by different mechanisms. Therefore, after examining clinical studies, it can be used as an effective drug for treating CRC.
... Rapamycin forms a complex with FKBP12 and binds to the rapamycin/FKBP12 binding domain in mTOR, resulting in RAPTOR dissociation and mTORC1 inactivation ( Figure 6) [101]. Thus, the allosteric inhibition of mTORC1 activity using rapamycin can increase tumor autophagy and reduce tumor growth by inducing cell death [102]. However, results in clinical trials for the treatment of cancer have been less than promising due to its poor solubility and pharmacokinetic properties. ...
... The effects of PF-06409577 are significantly more potent than traditional activators, such as metformin, representing significant advances in this field (Table 2). In addition to metformin, other drugs, such as AICAR, CRO15, α-hederin, phenformin, 2-deoxy-D-glucose (2DG), A-769662 or salicylate, stimulate autophagy through direct or indirect AMPK activation [102,107]. However, their specific mechanisms of action and possible adverse effects have not yet been fully elucidated and evaluated. ...
Autophagy, the process that enables the recycling and degradation of cellular components, is essential for homeostasis, which occurs in response to various types of stress. Autophagy plays an important role in the genesis and evolution of osteosarcoma (OS). The conventional treatment of OS has limitations and is not always effective at controlling the disease. Therefore, numerous researchers have analyzed how controlling autophagy could be used as a treatment or strategy to reverse resistance to therapy in OS. They highlight how the inhibition of autophagy improves the efficacy of chemotherapeutic treatments and how the promotion of autophagy could prove positive in OS therapy. The modulation of autophagy can also be directed against OS stem cells, improving treatment efficacy and preventing cancer recurrence. Despite promising findings, future studies are needed to elucidate the molecular mechanisms of autophagy and its relationship to OS, as well as the mechanisms underlying the functioning of autophagic modulators. Careful evaluation is required as autophagy modulation may have adverse effects on normal cells, and the optimization of autophagic modulators for use as drugs in OS is imperative.
... The p-toluene sulfonyl guided ED to sulfonamide receptors on ER and was decomposed by carboxylesterases, resulting in the release of DOX from ED. [4,16,17] It was reported that 3-methyladenine could inhibit the formation of a double membrane, named phagophore, thereby suppressing the formation of autophagosome. [18,19] Thus, we denoted 3-methyladenine as the autophagy inhibitor (AP I ). Rapamycin was reported to induce autophagosome formation and the subsequent fusion of lysosomes and autophagosomes. ...
Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER‐targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER‐related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER‐targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial–mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER‐targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca²⁺ release from the ER and functions as a cascade amplifier of ER dysfunction, which accelerates Ca²⁺ release, resulting in immunogenic cell death (ICD) induction and eventually triggering immune responses. Together, ER‐targeting therapy benefits from the autophagy‐enhancing strategy more than the autophagy‐inhibiting strategy for antitumor and antimetastasis treatment.
... Autophagy is a process still not completely understood, but known to play a role in cancer progression and metastasis [42]. The most important features of this process are associated with microtubule-associated proteins 1A/1B light chain 3A and 3B (LC3A and LC3B), as well as Beclin-1. ...
A series of new ursolic acid (UA) derivatives substituted with various amino acids (AAs) or dipeptides (DP) at the C-3 position of the steroid skeleton was designed and synthesized. The compounds were obtained by the esterification of UA with the corresponding AAs. The cytotoxic activity of the synthesized conjugates was determined using the hormone-dependent breast cancer cell line MCF-7 and the triple-negative breast cancer cell line MDA. Three derivatives (L-seryloxy-, L-prolyloxy-and L-alanyl-L-isoleucyloxy-) showed micromolar IC 50 values and reduced the concentrations of matrix metalloproteinases 2 and 9. Further studies revealed that for two compounds (L-seryloxy-and L-alanyl-L-isoleucyloxy-), a possible mechanism of their antiproliferative action is the activation of caspase-7 and the proapoptotic Bax protein in the apoptotic pathway. The third compound (L-prolyloxy-derivative) showed a different mechanism of action as it induced autophagy as measured by an increase in the concentrations of three autophagy markers: LC3A, LC3B, and beclin-1. This derivative also showed statistically significant inhibition of the proinflammatory cy-tokines TNF-α and IL-6. Finally, for all synthesized compounds, we computationally predicted their ADME properties as well as performed molecular docking to the estrogen receptor to assess their potential for further development as anticancer agents.
... The interaction between these two cellular events drew the attention of scientists. Autophagy is a self-degradation and self-maintenance process in eukaryotic cells that plays a crucial role in removing damaged organelles, proteins, and cell fragments (29). ...
Mycobacterium tuberculosis (Mtb) continues to pose a significant threat to global health because it causes granulomas and systemic inflammatory responses during active tuberculosis (TB). Mtb can induce macrophage pyroptosis, which results in the release of IL-1β and causes tissue damage, thereby promoting its spread. In the absence of anti-TB drugs, host-directed therapy (HDT) has been demonstrated to be an effective strategy against TB. In this study, we used an in vitro Mtb-infected macrophage model to assess the effect of baicalein, derived from Scutellariae radix, on pyroptosis induced in Mtb-infected macrophages. Further, we investigated the molecular mechanisms underlying the actions of baicalein. The results of the study suggest that baicalein inhibits pyroptosis in Mtb-infected macrophages by downregulating the assembly of AIM2 and NLRP3 inflammasome and promoting autophagy. Further research has also shown that the mechanism by which baicalein promotes autophagy may involve the inhibition of the activation of the Akt/mTOR pathway and the inhibition of the AIM2 protein, which affects the levels of CHMP2A protein required to promote autophagy. Thus, our data show that baicalein can inhibit Mtb infection-induced macrophage pyroptosis and has the potential to be a new adjunctive HDT drug. IMPORTANCE Current strategies for treating drug-resistant tuberculosis have limited efficacy and undesirable side effects; hence, research on new treatments, including innovative medications, is required. Host-directed therapy (HDT) has emerged as a viable strategy for modulating host cell responses in order to enhance protective immunity against infections. Baicalein, extracted from Scutellariae radix, was shown to inhibit pyroptosis caused by Mycobacterium tuberculosis-infected macrophages and was associated with autophagy. Our findings reveal that baicalein can be used as an adjunctive treatment for tuberculosis or other inflammatory diseases by regulating immune function and enhancing the antibacterial ability of the host. It also provides a new idea for exploring the anti-inflammatory mechanism of baicalein.
... Chloroquine is undergoing preclinical studies for metastatic prostate cancer and non-small cell lung cancer (NSCLC) treatment. Hydroxychloroquine, verteporfin, and clarithromycin are under clinical investigation [28]. FV-429 exerts a dual ability to induce apoptosis and autophagy blockage. ...
Combining chemotherapy with immunotherapy still remains a regimen in anticancer therapy. Novel 4-thiazolidinone-bearing hybrid molecules possess well-documented anticancer activity, and together with anti-HER2 antibodies, may represent a promising strategy in treating patients with gastric cancer with confirmed human epidermal growth factor receptor 2 (HER2) expression. The aim of the study was to synthesize a new 4-thiazolidinone derivative (Les-4367) and investigate its molecular mechanism of action in combination with trastuzumab or pertuzumab in human AGS gastric cancer cells. AGS cell viability and antiproliferative potential were examined. The effect of the tested combinations as well as monotherapy on apoptosis and autophagy was also determined. Metalloproteinase-2 (MMP-2), intercellular adhesion molecule 1 (ICAM-1), pro-inflammatory and anti-inflammatory cytokine concentrations were also demonstrated by the ELISA technique. We proved that pertuzumab and trastuzumab were very effective in increasing the sensitivity of AGS gastric cancer cells to novel Les-4367. The molecular mechanism of action of the tested combination is connected with the induction of apoptosis. Additionally, the anticancer activity is not associated with the autophagy process. Decreased concentrations of pro-inflammatory cytokines, MMP-2 and ICAM-1—were observed. The novel combination of drugs based on anti-HER2 antibodies with Les-4367 is a promising strategy against AGS gastric cancer cells.
