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Autophagy is a normal physiological process that aids the recycling of cellular nutrients, assisting the cells to cope with stressed conditions. However, autophagy's effect on cancer, including glioma, is uncertain and involves complicated molecular mechanisms. Several contradictory reports indicate that autophagy may promote or suppress glioma growth and progression. Autophagy inhibitors potentiate the efficacy of chemotherapy or radiation therapy in glioma. Numerous compounds stimulate autophagy to cause glioma cell death. Autophagy is also involved in the therapeutic resistance of glioma. This review article aims to detangle the complicated molecular mechanism of autophagy to provide a better perception of the two-sided role of autophagy in glioma and its therapeutic implications. The protein and epigenetic modulators of the cytoprotective and cytotoxic role of autophagy are described in this article. Moreover, several signaling pathways are associated with autophagy and its effects on glioma. We have reviewed the molecular pathways and highlighted the signaling axis involved in cytoprotective and cytotoxic autophagy. Additionally, this article discusses the role of autophagy in therapeutic resistance, including glioma stem cell maintenance and tumor microenvironment regulation. It also summarizes several investigations on the anti-glioma effects of autophagy modulators to understand the associated mechanisms and provide insights regarding its therapeutic implications.
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Breast cancer, the most frequent female malignancy, is often curable when detected at an early stage. The treatment of metastatic breast cancer is more challenging and may be unresponsive to conventional therapy. Immunotherapy is crucial for treating metastatic breast cancer, but its resistance is a major limitation. The tumor microenvironment (TME) is vital in modulating the immunotherapy response. Various tumor microenvironmental components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), are involved in TME modulation to cause immunotherapy resistance. This review highlights the role of stromal cells in modulating the breast tumor microenvironment, including the involvement of CAF-TAM interaction, alteration of tumor metabolism leading to immunotherapy failure, and other latest strategies, including high throughput genomic screening, single-cell and spatial omics techniques for identifying tumor immune genes regulating immunotherapy response. This review emphasizes the therapeutic approach to overcome breast cancer immune resistance through CAF reprogramming, modulation of TAM polarization, tumor metabolism, and genomic alterations.
Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Microambiente Tumoral , Feminino , Humanos , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/efeitos dos fármacosRESUMO
Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed prostate cancer stem cells (PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs; methods for isolation and enrichment of PCSCs; and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.
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Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Diferenciação Celular , Transdução de Sinais , Progressão da Doença , Células-Tronco Neoplásicas/patologiaRESUMO
Temozolomide (TMZ) is the leading chemotherapeutic agent used for glioma therapy due to its good oral absorption and blood-brain barrier permeability. However, its anti-glioma efficacy may be limited due to its adverse effects and resistance development. O6-Methylguanine-DNA-methyltransferase (MGMT), an enzyme associated with TMZ resistance, is activated via the NF-κB pathway, which is found to be upregulated in glioma. TMZ also upregulates NF-κB signaling like many other alkylating agents. Magnolol (MGN), a natural anti-cancer agent, has been reported to inhibit NF-κB signaling in multiple myeloma, cholangiocarcinoma, and hepatocellular carcinoma. MGN has already shown promising results in anti-glioma therapy. However, the synergistic action of TMZ and MGN has not been explored. Therefore, we investigated the effect of TMZ and MGN treatment in glioma and observed their synergistic pro-apoptotic action in both in vitro and in vivo glioma models. To explore the mechanism of this synergistic action, we found that MGN inhibits MGMT enzyme both in vitro and in vivo glioma. Next, we established the link between NF-κB signaling and MGN-induced MGMT inhibition in glioma. MGN inhibits the phosphorylation of p65, a subunit of NF-κB, and its nuclear translocation to block NF-κB pathway activation in glioma. MGN-induced NF-κB inhibition results in the transcriptional inhibition of MGMT in glioma. TMZ and MGN combinatorial treatment also impedes p65 nuclear translocation to inhibit MGMT in glioma. We observed a similar effect of TMZ and MGN treatment in the rodent glioma model. Thus, we concluded that MGN potentiates TMZ-induced apoptosis in glioma by inhibiting NF-κB pathway-mediated MGMT activation.
Assuntos
Glioma , NF-kappa B , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , NF-kappa B/metabolismo , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Metilases de Modificação do DNA/uso terapêutico , Proteínas Supressoras de Tumor/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/uso terapêuticoRESUMO
Chemoresistance is a primary cause of breast cancer treatment failure, and protein-protein interactions significantly contribute to chemoresistance during different stages of breast cancer progression. In pursuit of novel biomarkers and relevant protein-protein interactions occurring during the emergence of breast cancer chemoresistance, we used a computational predictive biological (CPB) approach. CPB identified associations of adhesion molecules with proteins connected with different breast cancer proteins associated with chemoresistance. This approach identified an association of Integrin ß1 (ITGB1) with chemoresistance and breast cancer stem cell markers. ITGB1 activated the Focal Adhesion Kinase (FAK) pathway promoting invasion, migration, and chemoresistance in breast cancer by upregulating Erk phosphorylation. FAK also activated Wnt/Sox2 signaling, which enhanced self-renewal in breast cancer. Activation of the FAK pathway by ITGB1 represents a novel mechanism linked to breast cancer chemoresistance, which may lead to novel therapies capable of blocking breast cancer progression by intervening in ITGB1-regulated signaling pathways.
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Neoplasias da Mama , Integrina beta1 , Feminino , Humanos , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Integrina beta1/metabolismoRESUMO
Glioma is difficult-to-treat because of its infiltrative nature and the presence of the blood-brain barrier. Temozolomide is the only FDA-approved drug for its management. Therefore, finding a novel chemotherapeutic agent for glioma is of utmost importance. Magnolol, a neolignan, has been known for its apoptotic role in glioma. In this work, we have explored a novel anti-glioma mechanism of Magnolol associated with its role in autophagy modulation. We found increased expression levels of Beclin-1, Atg5-Atg12, and LC3-II and lower p62 expression in Magnolol-treated glioma cells. PI3K/AKT/mTOR pathway proteins were also downregulated in Magnolol-treated glioma cells. Next, we treated the glioma cells with Insulin, a stimulator of PI3K/AKT/mTOR signaling, to confirm that Magnolol induced autophagy by inhibiting this pathway. Insulin reversed the effect on Magnolol-mediated autophagy induction. We also established the same in in vivo glioma model where Magnolol showed an anti-glioma effect by inducing autophagy. To confirm the cytotoxic effect of Magnolol-induced autophagy, we used Chloroquine, a late-stage autophagy inhibitor. Chloroquine efficiently reversed the anti-glioma effects of Magnolol both in vitro and in vivo. Our study revealed the cytotoxic effect of Magnolol-induced autophagy in glioma, which was not previously reported. Additionally, Magnolol showed no toxicity in non-cancerous cell lines as well as rat organs. Thus, we concluded that Magnolol is an excellent candidate for developing new therapeutic strategies for glioma management.
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Antineoplásicos , Glioma , Insulinas , Lignanas , Ratos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Lignanas/farmacologia , Lignanas/uso terapêutico , Glioma/tratamento farmacológico , Glioma/metabolismo , Autofagia , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Insulinas/farmacologia , Insulinas/uso terapêutico , Linhagem Celular Tumoral , ApoptoseRESUMO
Development of fluorescent imaging probes is an important topic of research for the early diagnosis of cancer. Based on the difference between the cellular environment of tumor cells and normal cells, several "smart" fluorescent probes have been developed. In this work, a glycopolymer functionalized Förster resonance energy transfer (FRET) based fluorescent sensor is developed, which can monitor the pH change in cellular system. One-pot sequential reversible addition-fragmentation chain transfer (RAFT)polymerization technique is employed to synthesize fluorescent active triblock glycopolymer that can undergo FRET change on the variation of pH. A FRET pair, fluorescein o-acrylate (FA) and 7-amino-4-methylcoumarin (AMC) is linked via a pH-responsive polymer poly [2-(diisopropylamino)ethyl methacrylate] (PDPAEMA), which can undergo reversible swelling/deswelling under acidic/neutral condition. The presence of glycopolymer segment provides stability, water solubility, and specificity toward cancer cells. The cellular FRET experiments on cancer cells (MDA MB 231) and normal cells (3T3 fibroblast cells) demonstrate that the material is capable of distinguishing cells as a function of pH change.
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Neoplasias , Pontos Quânticos , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes , Polimerização , Concentração de Íons de HidrogênioRESUMO
Photodynamic therapy has emerged as a noninvasive treatment modality for several types of cancers. However, conventional hydrophobic photosensitizers (PS) suffer from low water solubility and poor tumor-targeting ability. Therefore, PS modified with glycopolymers can offer adequate water solubility, biocompatibility, and tumor-targeting ability due to the presence of multiple sugar units. In this study, a well-defined block copolymer poly(3-O-methacryloyl-d-glucopyranose)-b-poly(2-(4-formylbenzoyloxy)ethylmethacrylate) (PMAG-b-PFBEMA) containing pendant glucose and aldehyde units is synthesized via reversible addition-fragmentation chain transfer polymerization method. A water-soluble PS (toluidine blue O; TBO) and a potent anticancer drug, Doxorubicin (Dox) are introduced to the polymer backbone via acid-labile Schiff-base reaction (PMAG-b-PFBEMA_TBO_Dox). The PMAG-b-PFBEMA_TBO_Dox is then anchored on the surface of gold nanoparticles (AuNPs) via electrostatic interaction. This hybrid system exhibits excellent reactive oxygen species (ROS) generating ability under exposure of 630 nm light-emitting diode along with triggered release of Dox under the acidic pH of tumor cells. The in vitro cytotoxicity study on human breast cancer cell line, MDA MB 231, for this hybrid system shows promising results due to the synergistic effect of ROS and Dox released. Thus, this glycopolymer-based dual (chemo-photodynamic) therapy model can work as potential material for future therapeutics.
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Nanopartículas Metálicas , Nanopartículas , Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Doxorrubicina/química , Ouro/química , Ouro/farmacologia , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , ÁguaRESUMO
The Transforming growth factor-ß1 (TGF- ß1) in the tumor microenvironment (TME) is the major cytokine that acts as a mediator of tumor-stroma crosstalk, which in fact has a dual role in either promoting or suppressing tumor development. The cancer-associated fibroblasts (CAFs) are the major cell types in the TME, and the interaction with most of the epithelial cancers is the prime reason for cancer survival. However, the molecular mechanisms, associated with the TGF- ß1 induced tumor promotion through tumor-CAF crosstalk are not well understood. In the Reverse Warburg effect, CAFs feed the adjacent cancer cells by lactate produced during the aerobic glycolysis. We hypothesized that the monocarboxylate transporter, MCT4 which is implicated in lactate efflux from the CAFs, must be overexpressed in the CAFs. Contextually, to explore the role of TGF- ß1 in the hypoxia-induced autophagy in CAFs, we treated CoCl2 and external TGF- ß1 to the human dermal fibroblasts and L929 murine fibroblasts. We demonstrated that hypoxia accelerated the TGF- ß1 signaling and subsequent transformation of normal fibroblasts to CAFs. Moreover, we elucidated that synergistic induction of autophagy by hypoxia and TGF- ß1 upregulate the aerobic glycolysis and MCT4 expression in CAFs. Furthermore, we showed a positive correlation between glucose consumption and MCT4 expression in the CAFs. Autophagy was also found to be involved in the EMT in hypoxic CAFs. Collectively, these findings reveal the unappreciated role of autophagy in TME, which enhances the CAF transformation and that promotes tumor migration and metastasis via the reverse Warburg effect.
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Autofagia , Fibroblastos Associados a Câncer , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Neoplasias , Fator de Crescimento Transformador beta1/metabolismo , Animais , Fibroblastos Associados a Câncer/patologia , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Hipóxia/metabolismo , Ácido Láctico/metabolismo , Camundongos , Neoplasias/patologia , Microambiente Tumoral , Regulação para CimaRESUMO
Sox family of transcriptional factors play essential functions in development and are implicated in multiple clinical disorders, including cancer. Sox2 being their most prominent member and performing a critical role in reprogramming differentiated adult cells to an embryonic phenotype is frequently upregulated in multiple cancers. High Sox2 levels are detected in breast tumor tissues and correlate with a worse prognosis. In addition, Sox2 expression is connected with resistance to conventional anticancer therapy. Together, it can be said that inhibiting Sox2 expression can reduce the malignant features associated with breast cancer, including invasion, migration, proliferation, stemness, and chemoresistance. This review highlights the critical roles played by the Sox gene family members in initiating or suppressing breast tumor development, while primarily focusing on Sox2 and its role in breast tumor initiation, maintenance, and progression, elucidates the probable mechanisms that control its activity, and puts forward potential therapeutic strategies to inhibit its expression.
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Neoplasias da Mama , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genéticaRESUMO
We demonstrated for the first time without any chemical modification the two-photon absorption (TPA) cross-section can be enhanced and red-shifted to the near-infrared (NIR) region by the ground-state proton-transfer (GSPT) process. Using GSPT, we developed a simple binol-based aggregation-induced emission (AIE)-fluorogenic phototrigger having a large two-photon uncaging cross-section in the "phototherapeutic window". As a proof of concept, we showed our phototrigger for the release of two different anticancer drugs in the NIR region.
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The use of medicinal plants is as ancient as human civilization. The development of phytochemistry and pharmacology facilitates the identification of natural bioactive compounds and their mechanisms of action, including against cancer. The efficacy and the safety of a bioactive compound depend on its optimal delivery to the target site. Most natural bioactive compounds (phenols, flavonoids, tannins, etc) are unable to reach their target sites due to their low water solubility, less cellular absorption, and high molecular weight, leading to their failure into clinical translation. Therefore, many scientific studies are going on to overcome the drawbacks of natural products for clinical applications. Several studies in India, as well as worldwide, have proposed the development of natural products-based nanoformulations to increase their efficacy and safety profile for cancer therapy by improving the delivery of natural bioactive compounds to their target site. Therefore, we are trying to discuss the development of natural products-based nanoformulations in India to improve the efficacy and safety of natural bioactive compounds against cancer.
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Produtos Biológicos , Neoplasias , Plantas Medicinais , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Flavonoides , Humanos , Neoplasias/tratamento farmacológico , SolubilidadeRESUMO
We report a two-photon responsive drug delivery system (DDS), namely, p-hydroxyphenacyl-naphthalene-chlorambucil (pHP-Naph-Cbl), having a two-photon absorption (TPA) cross-section of ≥20 GM in the phototherapeutic window (700 nm). Our DDS exhibited both AIE and ESIPT phenomena, which were utilized for the real-time monitoring of anti-cancer drug release.
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Antineoplásicos Alquilantes/química , Clorambucila/química , Portadores de Fármacos/química , Naftalenos/química , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/metabolismo , Clorambucila/farmacologia , Liberação Controlada de Fármacos , Humanos , Luz , Células MCF-7 , Microscopia Confocal , FótonsRESUMO
In this work, we depleted glutathione (GSH) by releasing SO2 with internal stimulus GSH itself, and also selectively marked the cancer cells followed by release of anticancer drug using another orthogonal stimulus i.e., two-photon (TP) NIR light by a single naphthalene based chromophore (TP absorbance 77 GM and uncaging cross-section 21 GM). We demonstrated the improved therapeutic efficacy of chlorambucil by the stepwise dual stimuli approach and dual surveillance of both the drug uncaging process in real-time using in vitro studies.
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Alquilantes/farmacologia , Antineoplásicos Alquilantes/farmacologia , Clorambucila/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Naftalenos/farmacologia , Fótons , Alquilantes/química , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/química , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/metabolismo , Humanos , Raios Infravermelhos , Estrutura Molecular , Naftalenos/química , Imagem Óptica , Dióxido de Enxofre/metabolismoRESUMO
Glioma is one of the most perplexing cancers because of its infiltrating nature, molecular signaling, and location in central nervous system. Blood-brain barrier acts as a natural barrier to the glioma making it difficult to access by conventional chemotherapy. Clinicians are using natural compounds or their derivatives for several diseases including different cancers. However, the feasibility of using natural compounds in glioma is not explored in details. Natural compounds can act over a wide variety of signaling pathways such as survival and metabolic pathways and induce cell death. Some of the natural agents have additional benefits of crossing biological barriers such as blood-brain barrier with ease having few or no impact on the surrounding healthy cells. All of these benefits make natural compounds a prospective candidate for the glioma management. This article evaluates the benefits of using natural compounds for glioma therapy and their possible mechanism of actions. We have discussed the natural compounds assessed currently for glioma therapy and proposed a few novel natural compounds with potential antiglioma effect based on their mechanism of action.