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Globally, cancer is the most prevalent chronic disease-related cause of death. Although there are many anticancer drugs, some of them have adverse effects. Due to their limited side effects, natural products are preferred over synthetic drugs. Andrographolide and its derivatives are known to be potent anticancer agents. In this context, sixteen novel 3,19-(NH-3-aryl-pyrazole) acetals of andrographolide and isoandrographolide (1a-1h, 2a-2g, 2i) from 3-aryl-1-H-pyrazole-4-carboxaldehydes (a-i) were synthesized. All the synthesized compounds were characterized using 1H NMR, 13C NMR, HRMS, FT-IR, and UV-vis spectroscopy. All the compounds were evaluated against a panel of 60 different human cancer cell lines for their anticancer potential at NCI, USA. Four compounds, having promising GI50s (50% growth inhibitory activity) on all 60-cell lines were selected for further in vitro studies. Out of these four compounds, compound 1g exhibited the best IC50 (3.08 µM) against the colon cancer cell line, HCT-116. Cell cycle analysis, annexin V-FITC/PI, and ROS assays revealed that the apoptosis of HCT-116 cells induced by compound 1g could be mainly attributed to the elevated levels of intracellular ROS. Further, the structure-activity relationship revealed that the pyrazole moiety of andrographolide plays a key role in their anticancer properties. These compounds were further examined for in silico ADMET and Lipinski characteristics to assess their potential as lead compounds.
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Tumour cells secrete various proangiogenic factors like VEGF, PDGF, and EGF that result in the formation of highly vascularized tumours with an immunosuppressive tumour microenvironment. As tumour growth and metastasis are highly dependent on angiogenesis, targeting tumour vasculature along with rapidly dividing tumour cells is a potential approach for cancer treatment. Here, we specifically engineered sub-100 sized nanomicelles (DTX-CA4 NMs) targeting proliferation and angiogenesis using an esterase-sensitive phosphocholine-tethered docetaxel conjugate of lithocholic acid (LCA) (PC-LCA-DTX) and a poly(ethylene glycol) (PEG) derivative of an LCA-combretastatin A4 conjugate (PEG-LCA-CA4). DTX-CA4 NMs effectively inhibit the tumour growth in syngeneic (CT26) and xenograft (HCT116) colorectal cancer models, inhibit tumour recurrence, and enhance the percentage survival in comparison with individual drug-loaded NMs. DTX-CA4 NMs enhance the T cell-mediated anti-tumour immune response and DTX-CA4 NMs in combination with an immune checkpoint inhibitor, anti-PDL1 antibody, enhance the anti-tumour response. We additionally showed that DTX-CA4 NMs effectively attenuate the production of ceramide-1-phosphate, a key metabolite of the sphingolipid pathway, by downregulating the expression of ceramide kinase at both transcriptional and translational levels. Therefore, this study presents the engineering of effective DTX-CA4 NMs for targeting the tumour microenvironment that can be explored further for clinical applications.
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Proliferação de Células , Ceramidas , Docetaxel , Micelas , Neovascularização Patológica , Animais , Ceramidas/química , Ceramidas/farmacologia , Humanos , Camundongos , Proliferação de Células/efeitos dos fármacos , Docetaxel/farmacologia , Docetaxel/química , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ácido Litocólico/química , Ácido Litocólico/farmacologia , Polietilenoglicóis/química , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Estilbenos/química , Estilbenos/farmacologia , Células HCT116 , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Microambiente Tumoral/efeitos dos fármacos , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , AngiogêneseRESUMO
Cancer treatment is challenged due to immunosuppressive inflammatory tumour microenvironment (TME) caused by infiltration of tumour-promoting and inhibition of tumour-inhibiting immune cells. Here, we report the engineering of chimeric nanomicelles (NMs) targeting the cell proliferation using docetaxel (DTX) and inflammation using dexamethasone (DEX) that alters the immunosuppressive TME. We show that a combination of phospholipid-DTX conjugate and PEGylated-lipid-DEX conjugate can self-assemble to form sub-100 nm chimeric NMs (DTX-DEX NMs). Anti-cancer activities against syngeneic and xenograft mouse models showed that the DTX-DEX NMs are more effective in tumour regression, enhance the survival of mice over other treatment modes, and alter the tumour stroma. DTX-DEX NMs cause a significant reduction in myeloid-derived suppressor cells, alter the polarization of macrophages, and enhance the accumulation of cytotoxic CD4+ and CD8+ T cells in tumour tissues, along with alterations in cytokine expression. We further demonstrated that these DTX-DEX NMs inhibit the synthesis of prostaglandins, especially PGE2, by targeting the cyclooxygenase 2 that is partly responsible for immunosuppressive TME. Therefore, this study presents, for the first time, the engineering of lithocholic acid-derived chimeric NMs that affect the prostaglandin pathway, alter the TME, and mitigate tumour progression with enhanced mice survival.
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Antineoplásicos , Prostaglandinas , Humanos , Camundongos , Animais , Prostaglandinas/farmacologia , Linfócitos T CD8-Positivos , Docetaxel/uso terapêutico , Docetaxel/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Terapia de Imunossupressão , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
RAD54 and BLM helicase play pivotal roles during homologous recombination repair (HRR) to ensure genome maintenance. BLM amino acids (aa 181-212) interact with RAD54 and enhance its chromatin remodeling activity. Functionally, this interaction heightens HRR, leading to a decrease in residual DNA damage in colon cancer cells. This contributes to chemoresistance in colon cancer cells against cisplatin, camptothecin, and oxaliplatin, eventually promoting tumorigenesis in preclinical colon cancer mouse models. ChIP-Seq analysis and validation revealed increased BLM and RAD54 corecruitment on the MRP2 promoter in camptothecin-resistant colon cancer cells, leading to BLM-dependent enhancement of RAD54-mediated chromatin remodeling. We screened the Prestwick small-molecule library, with the intent to revert camptothecin- and oxaliplatin-induced chemoresistance by disrupting the RAD54-BLM interaction. Three FDA/European Medicines Agency-approved candidates were identified that could disrupt this interaction. These drugs bound to RAD54, altered its conformation, and abrogated RAD54-BLM-dependent chromatin remodeling on G5E4 and MRP2 arrays. Notably, the small molecules also reduced HRR efficiency in resistant lines, diminished anchorage-independent growth, and hampered the proliferation of tumors generated using camptothecin- and oxaliplatin-resistant colon cancer cells in both xenograft and syngeneic mouse models in BLM-dependent manner. Therefore, the 3 identified small molecules can serve as possible viable candidates for adjunct therapy in colon cancer treatment.
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Neoplasias do Colo , Resistencia a Medicamentos Antineoplásicos , Humanos , Animais , Camundongos , Oxaliplatina/farmacologia , Reparo do DNA , Camptotecina , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Proliferação de CélulasRESUMO
Cancer heterogeneity poses a significant hurdle to the successful treatment of the disease, and is being influenced by genetic inheritance, cellular and tissue biology, disease development, and response to therapy. While chemotherapeutic drugs have demonstrated effectiveness, their efficacy is impeded by challenges such as presence of resilient cancer stem cells, absence of specific biomarkers, and development of drug resistance. Often chemotherapy leads to a myriad of epigenetic, transcriptional and post-transcriptional alterations in gene expression as well as changes in protein expression, thereby leading to massive metabolic reprogramming. This review seeks to provide a detailed account of various transcriptional regulations, proteomic changes, and metabolic reprogramming in various cancer models in response to three primary chemotherapeutic interventions, docetaxel, carboplatin, and doxorubicin. Discussing the molecular targets of some of these regulatory events and highlighting their contribution in sensitivity to chemotherapy will provide insights into drug resistance mechanisms and uncover novel perspectives in cancer treatment.
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Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B+CD8+ T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.
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Hidrogéis , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Morte Celular Imunogênica , Linfócitos T CD8-Positivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ceramidas , Modelos Animais de Doenças , Imunossupressores , Resposta a Proteínas não Dobradas , Microambiente TumoralRESUMO
Breast cancer (luminal and triple-negative breast cancer [TNBC]) is the most common cancer among women in India and worldwide. Altered sphingolipid levels have emerged as a common phenomenon during cancer progression. However, these alterations are yet to be translated into robust diagnostic and prognostic markers for cancer. Here, we present the quantified sphingolipids of tumor and adjacent-normal tissues from patients of luminal (n = 70) and TNBC (n = 42) subtype from an Indian cohort using targeted liquid chromatography mass spectrometry. We recorded unique sphingolipid profiles that distinguished luminal and TNBC tumors in comparison to adjacent normal tissue by six-sphingolipid signatures. Moreover, systematic comparison of the profiles of luminal and TNBC tumors provided a unique five-sphingolipid signature distinguishing the two subtypes. We further identified key sphingolipids that can stratify grade II and grade III tumors of luminal and TNBC subtype as well as their lymphovascular invasion status. Therefore, we provide the right evidence to develop these candidate sphingolipids as widely acceptable marker/s capable of diagnosing luminal vs TNBC subtype of breast cancer, and predicting the disease severity by identifying the tumor grade.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias da Mama/patologia , Esfingolipídeos , Recidiva Local de Neoplasia , Receptores de Estrogênio , Receptores de Progesterona , Biomarcadores Tumorais/análiseRESUMO
Sphingolipids are key signaling biomolecules that play a distinct role in cell proliferation, migration, invasion, drug resistance, metastasis, and apoptosis. Triple-negative (ER-PR-HER2-) and triple-positive (ER+PR+HER2+) breast cancer (called TNBC and TPBC, respectively) subtypes reveal distinct phenotypic characteristics and responses to therapy. Here, we present the sphingolipid profiles of BT-474 and MDA-MB-231 breast cancer cell lines representing the TPBC and TNBC subtypes. We correlated the level of different classes of sphingolipids and the expression of their corresponding metabolizing enzymes with the cell proliferation and cell migration properties of BT-474 and MDA-MB-231 cells. Our results showed that each cell type exhibits a unique sphingolipid profile, and common enzymes such as ceramide kinase (CERK, responsible for the synthesis of ceramide-1-phosphates) are deregulated in these cell types. We showed that siRNA/small molecule-mediated inhibition of CERK can alleviate cell proliferation in BT-474 and MDA-MB-231 cells, and cell migration in MDA-MB-231 cells. We further demonstrated that nanoparticle-mediated delivery of CERK siRNA and hydrogel-mediated sustained delivery of CERK inhibitor to the tumor site can inhibit tumor progression in BT-474 and MDA-MB-231 tumor models. In summary, distinct sphingolipid profiles of TPBC and TNBC representing cell lines provide potential therapeutic targets such as CERK, and nanoparticle/hydrogel mediated pharmacological manipulations of such targets can be explored for future cancer therapeutics.
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Proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) are critical mediators of inflammatory bowel disease pathogenesis, and are important targets to restore intestinal homeostasis. Herein, we present the engineering and screening of gemini lipid nanoparticles (GLNPs) for siRNA delivery to colon epithelial cells, macrophages and dendritic cells, and their ability to deliver siRNA therapeutics to the inflamed gastrointestinal tract. We synthesized eight gemini cationic lipids by tethering two lithocholic acid molecules through 3'-hydroxyl- and 24'-carboxyl-derived ammonium groups using different polyalkylene spacers. Screening of GLNPs, composed of gemini cationic lipid and dioleoylphosphatidylethanolamine lipid, showed that GLNPs derived from gemini lipid G1 are the most effective in the delivery of siRNA across mammalian cell membranes with reduced toxicity. Gemini lipid G1-derived siRNA-GLNP complexes (siGLNPs) can effectively reduce gene expression, and are stable in simulated gastric fluid. The delivery of TNF-α siRNA using siGLNPs can mitigate gut inflammation in a dextran sodium sulfate-induced murine inflammation model. As CD4+ T cells, especially Th17 cells, are key mediators of gut inflammation, we further showed that these siGLNPs inhibit infiltration and differentiation of CD4+ T cells to Th17 and Treg cells. Therefore, this study highlights the potential of GLNPs derived from lithocholic acid-derived gemini cationic lipids for the development of next-generation nucleic acid delivery vehicles.
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Compostos de Amônio , Fator de Necrose Tumoral alfa , Animais , Linfócitos T CD4-Positivos , Cátions , Citocinas , Dextranos , Inflamação , Lipídeos , Lipossomos , Ácido Litocólico , Mamíferos/genética , Camundongos , Nanopartículas , RNA Interferente PequenoRESUMO
Antiangiogenic therapy in combination with chemotherapeutic agents is an effective strategy for cancer treatment. However, this combination therapy is associated with several challenges including non-specific biodistribution leading to systemic toxicity. Biomaterial-mediated codelivery of chemotherapeutic and anti-angiogenic agents can exploit their passive and active targeting abilities, leading to improved drug accumulation at the tumor site and therapeutic outcomes. In this review, we present the progress made in the field of engineered biomaterials for codelivery of chemotherapeutic and antiangiogenic agents. We present advances in engineering of liposome/hydrogel/micelle-based biomaterials for delivery of combination of anticancer and anti-angiogenesis drugs, or combination of anticancer and siRNA targeting angiogenesis, and targeted nanoparticles. We then present our perspective on developing strategies for targeting angiogenesis and cell proliferation for cancer therapy.
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Antineoplásicos , Nanopartículas , Neoplasias , Humanos , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Distribuição Tecidual , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Proliferação de Células , Sistemas de Liberação de MedicamentosRESUMO
Infections caused by multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) pose major challenges for treatment due to the acquired, adaptive, and intrinsic resistance developed by the bacteria. Accumulation of mutations, the ability to form biofilms, and the presence of lipopolysaccharides in the outer bacterial membranes are the key mechanisms of drug resistance. Here, we show that a polyaspartate-derived synthetic antimicrobial polymer (SAMP) with a hexyl chain (TAC6) is an effective adjuvant for a hydrophobic antibiotic, rifampicin. Our in vitro studies demonstrated that the combination of TAC6 and rifampicin is effective against clinically isolated multidrug-resistant strains of P. aeruginosa. Membrane permeabilization studies showed that TAC6 allows the permeabilization of bacterial membranes, and the accumulation of rifampicin inside the cells, thereby enhancing its activity. The combination of TAC6 and rifampicin can also degrade the P. aeruginosa biofilms, and therefore can mitigate the adaptive resistance developed by bacteria. We further demonstrated that the combination of TAC6 and rifampicin can clear P. aeruginosa-mediated wound infections effectively. Therefore, our study showed polyaspartate-derived SAMP to be an effective antibiotic adjuvant against P. aeruginosa infections.
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Anti-Infecciosos , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Biofilmes , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana , Peptídeos , Polímeros/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Rifampina/farmacologia , Rifampina/uso terapêuticoRESUMO
Biomedical device or implant-associated infections caused by pathogenic bacteria are a major clinical issue, and their prevention and/or treatment remains a challenging task. Infection-resistant antimicrobial coatings with impressive cytocompatibility offer a step towards addressing this problem. Herein, we report a new strategy for constructing highly antibacterial as well as cytocompatible mixed polymer brushes onto the surface of 3D printed scaffold made of biodegradable tartaric acid-based aliphatic polyester blends. The mixed brushes were nothing but a combination of poly(3-dimethyl-(methacryloyloxyethyl) ammonium propane sulfonate) (polyDMAPS) and poly((oligo ethylene glycol) methyl ether methacrylate) (polyPEGMA) with varying chain length (n) of the ethylene glycol unit (n = 1, 6, 11, and 21). Both homo and copolymeric brushes of polyDMAPS with polyPEGMA exhibited antibacterial efficacy against both Gram positive and Gram negative pathogens such as E. coli (Escherichia coli) and S. aureus (Staphylococcus aureus) because of the combined action of bacteriostatic effects originating from strongly hydrated layers present in zwitterionic (polyDMAPS) and hydrophilic (polyPEGMA) copolymer brushes. Interestingly, a mixed polymer brush comprising polyDMAPS and polyPEGMA (ethylene glycol chain unit of 21) at 50/50 ratio provided zero bacterial growth and almost 100% cytocompatibility (tested using L929 mouse fibroblast cells), making the brush-modified biodegradable substrate an excellent choice for an infection-resistant and cytocompatible surface. An attempt was made to understand their extraordinary performance with the help of contact angle, surface charge analysis and nanoindentation study, which revealed the formation of a hydrophilic, almost neutral, very soft surface (99.99% reduction in hardness and modulus) after modification with the mixed brushes. This may completely suppress bacterial adhesion. Animal studies demonstrated that these brush-modified scaffolds are biocompatible and can mitigate wound infections. Overall, this study shows that the fascinating combination of an infection-resistant and cytocompatible surface can be generated on biodegradable polymeric surfaces by modulating the surface hardness, flexibility and hydrophilicity by selecting appropriate functionality of the copolymeric brushes grafted onto them, making them ideal non-leaching, anti-infective, hemocompatible and cytocompatible coatings for biodegradable implants.
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Anti-Infecciosos , Infecção dos Ferimentos , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Escherichia coli , Etilenoglicóis , Camundongos , Polímeros/química , Staphylococcus aureus , Propriedades de SuperfícieRESUMO
Meta-analysis of transcripts in colon adenocarcinoma patient tissues led to the identification of a DNA damage responsive miR signature called DNA damage sensitive miRs (DDSMs). DDSMs were experimentally validated in the cancerous colon tissues obtained from an independent cohort of colon cancer patients and in multiple cellular systems with high levels of endogenous DNA damage. All the tested DDSMs were transcriptionally upregulated by a common intestine-specific transcription factor, CDX2. Reciprocally, DDSMs were repressed via the recruitment of HDAC1/2-containing complexes onto the CDX2 promoter. These miRs downregulated multiple key targets in the DNA damage response (DDR) pathway, namely BRCA1, ATM, Chk1 (also known as CHEK1) and RNF8. CDX2 directly regulated the DDSMs, which led to increased tumor volume and metastasis in multiple preclinical models. In colon cancer patient tissues, the DDSMs negatively correlated with BRCA1 levels, were associated with decreased probability of survival and thereby could be used as a prognostic biomarker. This article has an associated First Person interview with the first author of the paper.
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Adenocarcinoma , Neoplasias do Colo , MicroRNAs , Fator de Transcrição CDX2/genética , Neoplasias do Colo/genética , Dano ao DNA/genética , Proteínas de Ligação a DNA/genética , Humanos , MicroRNAs/genética , Fatores de Transcrição , Ubiquitina-Proteína LigasesRESUMO
Herein, we present the engineering of a supramolecular nanomicellar system that is composed of self-assembled units of the PEGylated lithocholic acid (LCA)-docetaxel (DTX) conjugate (LCA-DTX-PEG). We tethered a short polyethylene glycol unit to LCA and used an esterase-sensitive ester linkage between DTX and LCA. The LCA-DTX-PEG conjugate formed nanomicelles (LCA-DTX-PEG NMs) with â¼160 nm hydrodynamic diameter that are sensitive to cellular esterases and maximized the release of DTX under high esterase exposure. LCA-DTX-PEG NMs were found to be effective as the parent drug in breast cancer cells by stabilizing tubulin and arresting the cells in the G2/M phase. We determined the maximum tolerated dose (MTD) and systemic and vital organ toxicity of LCA-DTX-PEG NMs in mice, rats, and rabbits. LCA-DTX-PEG NMs showed a MTD of >160 mg kg-1 and are found to be safe in comparison with their parent FDA-approved drug formulation (Taxotere® or DTX-TS) that is highly toxic. LCA-DTX-PEG NMs effectively reduced the tumor volume and increased the survival of 4T1 tumor-bearing mice with improved blood circulation time of the drug and its higher accumulation in tumor tissues. Therefore, this study highlights the potential of PEGylated bile acid-drug conjugate based nanomicelles for the development of next generation cancer therapeutics.
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Antineoplásicos , Micelas , Animais , Antineoplásicos/uso terapêutico , Ácidos e Sais Biliares , Linhagem Celular Tumoral , Docetaxel , Portadores de Fármacos , Camundongos , Coelhos , RatosRESUMO
Global dysregulation of RNA splicing and imbalanced sphingolipid metabolism has emerged as promoters of cancer cell transformation. Here, we present specific signature of alternative splicing (AS) events of sphingolipid genes for each breast cancer subtype from the TCGA-BRCA dataset. We show that ceramide synthase 2 (CERS2) undergoes a unique cassette exon event specifically in Luminal B subtype tumors. We validated this exon 8 skipping event in Luminal B cancer cells compared to normal epithelial cells, and in patient-derived tumor tissues compared to matched normal tissues. Differential AS-based survival analysis shows that this AS event of CERS2 is a poor prognostic factor for Luminal B patients. As Exon 8 corresponds to catalytic Lag1p domain, overexpression of AS transcript of CERS2 in Luminal B cancer cells leads to a reduction in the level of very-long-chain ceramides compared to overexpression of protein-coding (PC) transcript of CERS2. We further demonstrate that this AS event-mediated decrease of very-long-chain ceramides leads to enhanced cancer cell proliferation and migration. Therefore, our results show subtype-specific AS of sphingolipid genes as a regulatory mechanism that deregulates sphingolipids like ceramides in breast tumors, and can be explored further as a suitable therapeutic target.
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Processamento Alternativo , Neoplasias da Mama/enzimologia , Movimento Celular , Proliferação de Células , Ceramidas/metabolismo , Proteínas de Membrana/metabolismo , Esfingosina N-Aciltransferase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Proteínas de Membrana/genética , Invasividade Neoplásica , Transdução de Sinais , Esfingosina N-Aciltransferase/genética , Transcriptoma , Proteínas Supressoras de Tumor/genéticaRESUMO
Chemotherapy is the primary option for the treatment of cancer, inflammation, and infectious diseases. Conventional drug delivery poses solubility and bioavailability challenges, systemic toxicity, non-specific targeting, and poor accumulation of chemotherapeutic drugs at the desired site. Nanotechnology has led to the development of various nanomaterials that have decreased the toxicity and increased the accumulation of drugs at the target site. Systemic administration of nanomaterials causes burst release and non-specific targeting of chemotherapeutics, leading to off-target organ toxicity. Drug delivery based on low molecular weight hydrogels (LMWHs) provides a suitable alternative for drug delivery due to their ability to entrap chemotherapeutic drugs. Injectable and biodegradable LMWHs allow the administration of chemotherapeutics with minimal invasion, allow the sustained release of chemotherapeutic drugs for long periods, and reduce the challenges of immunogenicity and low drug entrapment efficiency. Herein, we summarize the advances in the engineering of LMWHs for controlled and prolonged delivery of chemotherapeutics for cancer, infectious diseases, and inflammatory disorders.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Hidrogéis/química , Neoplasias/tratamento farmacológico , Engenharia de Proteínas/métodos , Engenharia Tecidual/métodos , Animais , Química Farmacêutica/métodos , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Inflamação , Teste de Materiais , Camundongos , Peso Molecular , Neoplasias/metabolismoRESUMO
In this study, we describe the engineering of sub-100â nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates. We further demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next-generation chemotherapeutic.
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Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Ácido Litocólico/análogos & derivados , Ácido Litocólico/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG , Desmetilação , Progressão da Doença , Docetaxel/síntese química , Docetaxel/farmacocinética , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Feminino , Ácido Litocólico/farmacocinética , Camundongos Endogâmicos BALB C , Micelas , Neoplasias/fisiopatologia , Tensoativos/síntese química , Tensoativos/farmacocinética , Tensoativos/uso terapêuticoRESUMO
The release of anticancer drugs in systemic circulation and their associated toxicity are responsible for the poor efficacy of chemotherapy. Therefore, the identification of new chemotherapeutic combinations designed to be released near the tumor site in a sustained manner has the potential to enhance the efficacy and reduce the toxicity associated with chemotherapy. Here, we present the identification of a combination of doxorubicin, a DNA-binding topoisomerase inhibitor, with a naturally occurring triterpenoid, celastrol, that induces a synergistic effect on the apoptosis of colon cancer cells. Hydrogel-mediated sustained release of a combination of doxorubicin and celastrol in a murine tumor model abrogates tumor proliferation, and increases the median survival with enhanced apoptosis and concurrent reduction in proliferation. Sphingolipid profiling (LC-MS/MS) of treated tumors showed that the combination of celastrol and doxorubicin induces global changes in the expression of sphingolipids with an increase in levels of ceramides. We further demonstrate that this dual drug combination induces a significant increase in the expression of ceramide synthase 1, 4, and 6, thereby increasing the level of ceramides that contribute to the synergistic apoptotic effect. Therefore, hydrogel-mediated localized delivery of a combination of celastrol and doxorubicin provides a new therapeutic combination that induces a sphingolipid-mediated synergistic effect against colon cancer.
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Neoplasias , Triterpenos , Animais , Ceramidas , Cromatografia Líquida , Doxorrubicina/farmacologia , Hidrogéis , Camundongos , Triterpenos Pentacíclicos , Espectrometria de Massas em Tandem , Triterpenos/farmacologia , Regulação para CimaRESUMO
Non-specific toxicity of chemotherapeutics and evolution of malignant tumors against them are major challenges for existing cancer chemotherapeutic regimens. Engineering of nanomaterials has attempted to minimize the toxicity of anticancer drugs, but systemic delivery of these nanomaterials still imposes many hurdles in their clinical use like burst release of chemotherapeutics and toxicity and immunogenicity associated with excipients of nanomaterials. However, there has been a surge in the development of natural and synthetic nanomaterials to deliver anticancer agents to the diseased (tumor) site as it can minimize the systemic circulation of anticancer drugs and reduce the toxicity-related challenges. Therefore, localized drug delivery is considered as the most effective way to deliver therapeutics but is further challenged by poor biodegradability, high immunogenicity, poor drug entrapment efficacy and inability to maintain sustained release of anticancer agents at the tumor site. This review maps out recent advancements in engineering of low molecular weight hydrogels derived from amino acid, fatty acyl, steroidal lipid and drug conjugated amphiphilic scaffolds. We have summarized the efforts for the development of molecular hydrogels in terms of biocompatibility, therapeutic potential and challenges associated with existing molecular hydrogels for cancer therapy.
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Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Hidrogéis/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Ácidos e Sais Biliares/administração & dosagem , Ácidos e Sais Biliares/química , Humanos , Hidrogéis/química , Lipídeos/administração & dosagem , Lipídeos/química , Peptídeos/administração & dosagem , Peptídeos/químicaRESUMO
Rapid proliferation of cancer cells assisted by endothelial cell-mediated angiogenesis and acquired inflammation at the tumor microenvironment (TME) lowers the success rate of chemotherapeutic regimens. Therefore, targeting these processes using localized delivery of a minimally toxic drug combination may be a promising strategy. Here, we present engineering of a biocompatible self-assembled lithocholic acid-dipeptide derived hydrogel (TRI-Gel) that can maintain sustained delivery of antiproliferating doxorubicin, antiangiogenic combretastatin-A4 and anti-inflammatory dexamethasone. Application of TRI-Gel therapy to a murine tumor model promotes enhanced apoptosis with a concurrent reduction in angiogenesis and inflammation, leading to effective abrogation of tumor proliferation and increased median survival with reduced drug resistance. In-depth RNA-sequencing analysis showed that TRI-Gel therapy induced transcriptome-wide alternative splicing of many genes responsible for oncogenic transformation including sphingolipid genes. We demonstrate that TRI-Gel therapy targets the reversal of a unique intron retention event in ß-glucocerebrosidase 1 (Gba1), thereby increasing the availability of functional Gba1 protein. An enhanced Gba1 activity elevates ceramide levels responsible for apoptosis and decreases glucosylceramides to overcome drug resistance. Therefore, TRI-Gel therapy provides a unique system that affects the TME via post-transcriptional modulations of sphingolipid metabolic genes, thereby opening a new and rational approach to cancer therapy.