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1.
ACS Chem Biol ; 19(7): 1433-1439, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38959478

RESUMO

Most of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to the poor prognosis, ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available to date for ALT positive cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homologous recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of SMARCAL1 by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led toward the increased localization of PML (promyelocytic leukemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukemia bodies) in ALT positive cell lines, increasing telomere replication stress and DNA damage at a genomic level. Induction of replication stress and hyper-recombinogenic phenotype in ALT positive cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT positive tumors. In accordance with this, our study will also provide a valuable insight toward the development of G4-based ALT therapeutics targeting SMARCAL1.


Assuntos
DNA Helicases , Quadruplex G , Neoplasias , Regiões Promotoras Genéticas , Telômero , Humanos , Telômero/genética , Telômero/metabolismo , DNA Helicases/metabolismo , DNA Helicases/genética , Neoplasias/genética , Linhagem Celular Tumoral , Replicação do DNA , Homeostase do Telômero
2.
Discov Oncol ; 14(1): 220, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38038865

RESUMO

Cancer stem cells (CSCs), being the primary contributors in tumor initiation, metastasis, and relapse, ought to have seminal roles in evasion of immune surveillance. Tumor-promoting CD4+CD25+FOXP3+ T-regulatory cells (Tregs) have been described to abolish host defense mechanisms by impeding the activities of other immune cells including effector T cells. However, whether CSCs can convert effector T cells to immune-suppressive Treg subset, and if yes, the mechanism underlying CSC-induced Treg generation, are limitedly studied. In this regard, we observed a positive correlation between breast CSC and Treg signature markers in both in-silico and immunohistochemical analyses. Mirroring the conditions during tumor initiation, low number of CSCs could successfully generate CD4+CD25+FOXP3+ Treg cells from infiltrating CD4+ T lymphocytes in a contact-independent manner. Suppressing the proliferation potential as well as IFNγ production capacity of effector T cells, these Treg cells might be inhibiting antitumor immunity, thereby hindering immune-elimination of CSCs during tumor initiation. Furthermore, unlike non-stem cancer cells (NSCCs), CSCs escaped doxorubicin-induced apoptosis, thus constituting major surviving population after three rounds of chemotherapy. These drug-survived CSCs were also able to generate CD4+CD25+FOXP3+ Treg cells. Our search for the underlying mechanism further unveiled the role of CSC-shed immune-suppressive cytokine TGFß, which was further increased by chemotherapy, in generating tumor Treg cells. In conclusion, during initiation as well as after chemotherapy, when NSCCs are not present in the tumor microenvironment, CSCs, albeit present in low numbers, generate immunosuppressive CD4+CD25+FOXP3+ Treg cells in a contact-independent manner by shedding high levels of immune-suppressive Treg-polarizing cytokine TGFß, thus escaping immune-elimination and initiating the tumor or causing tumor relapse.

3.
Front Immunol ; 14: 1295257, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38035101

RESUMO

Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.


Assuntos
Microambiente Tumoral , Macrófagos Associados a Tumor , Humanos , Macrófagos , Neovascularização Patológica , Recidiva
4.
ACS Appl Mater Interfaces ; 14(28): 31973-31985, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35792904

RESUMO

This article reports a novel and rational approach to convert waste cigarette filters (CFs), one of the largest sources of ocean pollution, into high-performance triboelectric nanogenerators (TENGs) and efficient CO2-capturing adsorbents. CFs are plasticized cellulose acetate, which take several years to degrade. To revalorize these fibers, selective amine surface functionalization is performed (10PAL-20T-CFs). For the proof of concept, when the modified fibers are employed in a TENG, it could generate an output voltage (96.63 V) and current (9.37 µA) that are, respectively, 43 and 8 times higher than those obtained employing the pristine CFs for the nanogenerator. The proposed TENG displays an instantaneous peak power of 3.75 mW, which is higher than that of many recently reported TENGs made from cellulose materials. Moreover, the TENG displayed outstanding durability to humidity and high-performance stability when it is subjected to cyclic loading (i.e., 12,000 cycles of loading-unloading). A 9 cm2 TENG could effectively light up 100 or more colored light-emitting diodes when it is manually pressed. Finally, the modified filter fibers show an excellent CO2 adsorption capacity of 1.93 mmol/g, which is 9.2 times higher than that obtained using the pristine fibers. These results demonstrate that hazardous wastes such as CFs can be upcycled into valuable resources.

5.
Appl Opt ; 60(31): 9906-9914, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34807194

RESUMO

Technological advancement has led to improvement in the design capabilities of astronomical spectrographs, allowing for high-precision spectroscopy, thereby expanding the realms of observational astronomy. High-resolution spectrographs use echelle gratings that operate in higher orders, giving more detailed spectra. Often, curvature and tilted lines are observed in the spectra, arising due to the design trade-offs of the respective spectrographs. Removal of these artifacts can help avoid wrong flux calculation and line centroid position misinterpretation, which can aid in a better prediction of the wavelength calibration model. In this paper we present a postprocessing technique that we developed to correct the observed curvature and tilt in the spectra. We have demonstrated the correction technique on Fabry-Perot and Th-Ar calibration spectra obtained from a Hanle echelle spectrograph, a Magellan Inamori Kyocera Echelle spectrometer, and a X-Shooter spectrograph.

7.
Sci Signal ; 13(654)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082288

RESUMO

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.


Assuntos
Aspirina/farmacologia , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
JNMA J Nepal Med Assoc ; 58(222): 122-124, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32335627

RESUMO

Quadruplet pregnancy is a pregnancy state where four fetuses grow simultaneously inside a mother's womb. Four fetuses developing in a womb is a challenge not only to the mother but to the obstetrician who has to calculate every risk associated with such pregnancy. High order pregnancy is considered a high risk pregnancy due to increase in maternal, fetal and neonatal morbidity and mortality. So a multidisciplinary approach with early involvement of neonatologists and anesthesiologists for the assessment of such case is essential for a successful obstetric outcome. Here we present a case report of 27 years G3P1L1A1 at 33 weeks 2 days of gestation with quadruplet pregnancy with previous lower segment Cesarian section with history of ovulation induction, delivered successfully via cesarean section with successful outcome of all 1 female and 3 male babies. Keywords: case report; cesarean section; fertility agent; multiple pregnancy; pregnancy; quadruplets.


Assuntos
Complicações na Gravidez , Gravidez de Quadrigêmeos , Adulto , Cesárea , Feminino , Humanos , Masculino , Gravidez , Resultado da Gravidez , Quadrigêmeos
9.
Free Radic Biol Med ; 152: 152-165, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32145302

RESUMO

A plethora of molecular strategies are employed by breast cancer stem cells (bCSCs) to evade chemotherapy-induced death signals, redox modulation being a crucial factor among those. Here, we observed that bCSCs are resistant to DNA damage and generate low ROS upon doxorubicin (Dox) treatment. Further exploration revealed inherently high NEIL2, a base excision repair (BER) enzyme that plays a key regulatory role in repairing DNA damage, in bCSCs. However, its role in modulating the redox status of bCSCs remains unexplored. In addition, Dox not only upregulates NEIL2 in bCSCs at both transcriptional and translational levels but also declines p300-induced acetylation thus activating NEIL2 and providing a protective effect against the stress inflicted by the genotoxic drug. However, when the redox status of bCSCs is altered by inducing high ROS, apoptosis of the resistant population is accomplished. Subsequently, when NEIL2 is suppressed in bCSCs, chemo-sensitization of the resistant population is enabled by redox reconditioning via impaired DNA repair. This signifies a possibility of therapeutically disrupting the redox balance in bCSCs to enhance their chemo-responsiveness. Our search for an inhibitor of NEIL2 revealed that vitamin B6, i.e., pyridoxine (PN), hinders NEIL2-mediated transcription-coupled repair process by not only decreasing NEIL2 expression but also inhibiting its association with RNA Pol II, thus stimulating DNA damage and triggering ROS. As a consequence of altered redox regulation, bCSCs become susceptible towards Dox, which then induces apoptosis via caspase cascade. These findings signify that PN enhances chemo-responsiveness of bCSCs via redox reconditioning.


Assuntos
Neoplasias da Mama , Piridoxina , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Doxorrubicina/farmacologia , Feminino , Humanos , Células-Tronco Neoplásicas , Oxirredução
10.
Sci Rep ; 9(1): 16913, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729456

RESUMO

Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin retards the same. A search for the underlying mechanism revealed that aspirin pre-treatment abrogates p300 binding both at TATA-box and initiator (INR) regions of mTOR promoter of CSCs, thereby impeding RNA polymerase II binding at those sites and repressing mTOR gene transcription. As a consequence of mTOR down-regulation, Akt is deactivated via dephosphorylation at Ser473 residue thereby activating Gsk3ß that in turn causes destabilization of Snail and ß-catenin, thus reverting epithelial to mesenchymal transition (EMT). However, alone aspirin fails to hinder migration since it does not inhibit the Integrin/Fak pathway, which is highly activated in NSCLC stem cells. On the other hand, in aspirin pre-treated CSCs, cisplatin stalls migration by hindering the integrin pathway. These results signify the efficacy of aspirin in sensitizing NSCLC stem cells towards the anti-migration effect of cisplatin. Cumulatively, our findings raise the possibility that aspirin might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to impede migration of NSCLC stem cells otherwise. This may consequently lead to the advancement of remedial outcome for the metastatic NSCLCs.


Assuntos
Antineoplásicos/farmacologia , Aspirina/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Pulmonares , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
11.
Apoptosis ; 24(11-12): 958-971, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31641961

RESUMO

Anoikis resistance is an essential property of cancer cells that allow the extra-cellular matrix-detached cells to survive in a suspended state in body fluid in order to metastasize and invade to distant organs. It is known that integrins play an important role in anoikis resistance, but detailed mechanisms are not well understood. Here we report that highly metastatic colon cancer cells showed a higher degree of anoikis resistance than the normal intestinal epithelial cells. These anoikis-resistant cancer cells express high-levels of integrin-α2, ß1, and activated EGFR in the anchorage-independent state than the anchorage-dependent state. In contrast, normal intestinal epithelial cells failed to elevate these proteins. Interestingly, a higher co-association of EGFR with integrin-α2ß1/-α5ß1 was observed on the surface of anoikis-resistant cells. Thus, in the absence of extra-cellular matrix, integrins in association with EGFR activates downstream effectors ERK and AKT and suppress Caspase-3 activation to induce anoikis resistance as was confirmed from the gene-ablation and pharmacological inhibitor studies. Interestingly, these anoikis-resistant cancer cells express high-level of cancer stem cell signatures (CD24, CD44, CD133, EpCAM) and pluripotent stem cell markers (OCT-4, SOX-2, Nanog) as well as drug-resistant pumps (ABCG2, MDR1, MRP1). Altogether, our findings unravel the interplay between integrin-α2ß1/-α5ß1 and EGFR in anoikis resistance and suggest that the resistant cells are cancer initiating or cancer stem cells, which may serve as a promising target to combat metastasis of cancer.


Assuntos
Anoikis , Neoplasias do Colo/metabolismo , Integrina alfa2beta1/metabolismo , Células-Tronco Neoplásicas/metabolismo , Antígeno AC133/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Anoikis/genética , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Integrina alfa2beta1/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteína Homeobox Nanog/metabolismo , Proteínas de Neoplasias/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXB1/metabolismo
12.
Biochemistry ; 58(15): 1975-1991, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30920805

RESUMO

The nuclease hypersensitive element III1 (NHE III1) upstream c-MYC promoter harbors a transcription-silencing G-quadruplex (Pu27) element. Dynamic turnover of various transcription factors (TFs) across Pu27 to control c-MYC transcription homeostasis is enigmatic. Here, we reveal that native Pu27 evolves truncated G-quadruplex isomers (Pu19, Pu22, Pu24, and Pu25) in cells that are optimal intracellular targets of specific TFs in a sequence- and structure-dependent manner. Nuclear magnetic resonance and isothermal titration calorimetry envisaged that NM23-H2 (nucleoside diphosphate kinase) and nucleolin induce conformational fluctuations in Pu27 to sample specific conformationally restricted conformer(s). Structural investigations revealed that the flanking guanines at 5'-Pu27 control solvent exposure at G-quartets upon NM23-H2 and nucleolin binding driving Pu27 unfolding and folding, respectively. Transient chromatin immunoprecipitations confirmed that NM23-H2 drives the conformation switch to Pu24 that outcompetes nucleolin recruitment. Similarly, nucleolin arrests Pu27 in the Pu22 conformer minimizing NM23-H2 binding at Pu27. hnRNPK (heterogeneous nuclear ribonucleoprotein K) positively regulates NM23-H2 and nucleolin association at Pu27 despite their antagonism. On the basis of these results, we simulated the transcription kinetics in a feed-forward loop in which the transcription output responds to hnRNPK-induced early activation via NM23-H2 association, which favors Pu24 formation at NHE III1 reducing nucleolin occupancy and driving quadruplex unfolding to initiate transcription. NM23-H2 further promotes hnRNPK deposition across NHE III1 altering Pu27 plasticity that finally enriches the nucleolin abundance to drive Pu22 formation and weaken NM23-H2 binding to extinguish transcription. This mechanism involves three positive feedback loops (NM23-H2-hnRNPK, NM23-H2-CNBP, and hnRNPK-nucleolin) and one negative feedback loop (NM23-H2-nucleolin) controlling optimal turnover and residence time of TFs at Pu27 to homeostatically regulate c-MYC transcription.


Assuntos
DNA/química , Quadruplex G , Homeostase , Proteínas Proto-Oncogênicas c-myc/química , Fatores de Transcrição/química , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/química , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Humanos , Isomerismo , Nucleosídeo NM23 Difosfato Quinases/química , Nucleosídeo NM23 Difosfato Quinases/genética , Nucleosídeo NM23 Difosfato Quinases/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Nucleolina
13.
Nanoscale ; 9(21): 7081-7093, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28513711

RESUMO

The excellent biocompatibility, biodegradability and chemo-thermal stability of poly(vinyl alcohol) (PVA) have been harnessed in diverse practical applications. These properties have motivated the fabrication of high performance PVA based nanofibers with adequate control over the micro and nano-architectures and surface chemical interactions. However, the high water solubility and hydrophilicity of the PVA polymer limits the application of the electrospun PVA nanofibers in aqueous environments owing to instantaneous dissolution. In this work, we report a novel yet facile concept for fabricating extremely light, fluffy, insoluble and stable three dimensional (3D) PVA fibrous scaffolds with/without coating for multifunctional purposes. While the solubility, morphology, fiber density and mechanical properties of nanofibers could be tuned by optimizing the cross-linking conditions, the surface chemical reactivity could be readily enhanced by coating with a polydopamine (pDA) bioinspired polymer without compromising the stability and innate properties of the native PVA fiber. The 3D pDA-PVA scaffolds exhibited super dye adsorption and constructive synergistic cell-material interactions by promoting healthy adhesion and viability of the human mesenchymal stem cells (hMSCs) within 3D micro-niches. We foresee the application of tunable PVA 3D as a highly adsorbent material and a scaffold material for tissue regeneration and drug delivery with close consideration of realistic in vivo parameters.

14.
Free Radic Biol Med ; 103: 35-47, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27940348

RESUMO

We find that PEG functionalized ZnO nanoparticles (NP) have anticancer properties primarily because of ROS generation. Detailed investigation revealed two consequences depending on the level of ROS - either DNA damage repair or apoptosis - in a time-dependent manner. At early hours of treatment, NP promote NEIL2-mediated DNA repair process to counteract low ROS-induced DNA damage. However, at late hours these NP produce high level of ROS that inhibits DNA repair process, thereby directing the cell towards apoptosis. Mechanistically at low ROS conditions, transcription factor Sp1 binds to the NEIL2 promoter and facilitates its transcription for triggering a 'fight-back mechanism' thereby resisting cancer cell apoptosis. In contrast, as ROS increase during later hours, Sp1 undergoes oxidative degradation that decreases its availability for binding to the promoter thereby down-regulating NEIL2 and impairing the repair mechanism. Under such conditions, the cells strategically switch to the p53-dependent apoptosis.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Óxido de Zinco/farmacologia , Antineoplásicos/síntese química , Neoplasias da Mama , DNA Glicosilases/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Nanopartículas Metálicas/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Polietilenoglicóis/síntese química , Espécies Reativas de Oxigênio/metabolismo , Óxido de Zinco/síntese química
15.
Sci Rep ; 6: 32979, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27622714

RESUMO

Tumor suppressor p53 preserves the genomic integrity by restricting anomaly at the gene level. The hotspots for mutation in half of all colon cancers reside in p53. Hence, in a p53-mutated cellular milieu targeting cancer cells may be achievable by targeting the paralogue(s) of p53. Here we have shown the effectiveness of crocetin, a dietary component, in inducing apoptosis of colon cancer cells with varying p53 status. In wild-type p53-expressing cancer cells, p53 in one hand transactivates BAX and in parallel up-regulates p53-induced death domain protein (PIDD) that in turn cleaves and activates BID through caspase-2. Both BAX and t-BID converge at mitochondria to alter the transmembrane potential thereby leading to caspase-9 and caspase-3-mediated apoptosis. In contrast, in functional p53-impaired cells, this phytochemical exploits p53-paralogue p73, which up-regulates FAS to cleave BID through FAS-FADD-caspase-8-pathway. These findings not only underline the phenomenon of functional switch-over from p53 to p73 in p53-impaired condition, but also validate p73 as a promising and potential target for cancer therapy in absence of functional p53.


Assuntos
Carotenoides/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 2/metabolismo , Caspase 8/metabolismo , Neoplasias Colorretais/patologia , Cisteína Endopeptidases/metabolismo , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteína de Domínio de Morte Associada a Fas/genética , Células HCT116 , Células HT29 , Humanos , Mutação , Transdução de Sinais/efeitos dos fármacos , Proteína Tumoral p73/metabolismo , Proteína Supressora de Tumor p53/genética , Vitamina A/análogos & derivados , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Receptor fas/metabolismo
16.
Sci Rep ; 6: 22335, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26928472

RESUMO

Promastigote form of Leishmania, an intracellular pathogen, delays phagosome maturation and resides inside macrophages. But till date limited study has been done to manipulate the phagosomal machinery of macrophages to restrict Leishmania growth. Attenuated Leishmania strain exposed RAW 264.7 cells showed a respiratory burst and enhanced production of pro-inflammatory mediators. The augmentation of pro-inflammatory activity is mostly attributed to p38 MAPK and p44/42 MAPK. In our study, these activated macrophages are found to induce phagosome maturation when infected with pathogenic Leishmania donovani. Increased co-localization of carboxyfluorescein succinimidyl ester labeled pathogenic L. donovani with Lysosome was found. Moreover, increased co-localization was observed between pathogenic L. donovani and late phagosomal markers viz. Rab7, Lysosomal Associated Membrane Protein 1, Cathepsin D, Rab9, and V-ATPase which indicate phagosome maturation. It was also observed that inhibition of V-type ATPase caused significant hindrance in attenuated Leishmania induced phagosome maturation. Finally, it was confirmed that p38 MAPK is the key player in acidification and maturation of phagosome in attenuated Leishmania strain pre-exposed macrophages. To our knowledge, this study for the first time reported an approach to induce phagosome maturation in L. donovani infected macrophages which could potentiate short-term prophylactic response in future.


Assuntos
Leishmania donovani/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose/prevenção & controle , Macrófagos/imunologia , Fagossomos/metabolismo , Animais , Mediadores da Inflamação/metabolismo , Leishmania donovani/crescimento & desenvolvimento , Leishmaniose/imunologia , Macrófagos/parasitologia , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo , Células RAW 264.7 , Vacinas Atenuadas , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Cancer Res ; 76(7): 2000-12, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26842876

RESUMO

Acquired chemoresistance has curtailed cancer survival since the dawn of chemotherapy. Accumulating evidence suggests a major role for cancer stem cells (CSC) in chemoresistance, although their involvement in acquired resistance is still unknown. The use of aspirin has been associated with reduced cancer risk and recurrence, suggesting that the anti-inflammatory drug may exert effects on CSCs. In this study, we investigated the contribution of CSCs to acquired chemoresistance of breast cancer and the avenues for reversing such effects with aspirin. We observed that the residual risk of recurrence was higher in breast cancer patients who had acquired chemoresistance. Treatment of preexisting CSCs with a genotoxic drug combination (5-fluorouracil, doxorubicin, and cyclophosphamide) generated an NFκB-IL6-dependent inflammatory environment that imparted stemness to nonstem cancer cells, induced multidrug resistance, and enhanced the migration potential of CSCs. Treatment with aspirin prior to chemotherapy suppressed the acquisition of chemoresistance by perturbing the nuclear translocation of NFκB in preexisting CSCs. Therefore, disruptions to the NFκB-IL6 feedback loop prevented CSC induction and sensitized preexisting CSCs to chemotherapy. Collectively, our findings suggest that combining aspirin and conventional chemotherapy may offer a new treatment strategy to improve recurrence-free survival of breast cancer patients. Cancer Res; 76(7); 2000-12. ©2016 AACR.


Assuntos
Aspirina/farmacologia , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Aspirina/metabolismo , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Humanos , Microscopia Confocal , Células-Tronco Neoplásicas/efeitos dos fármacos , Estudos Prospectivos , Estudos Retrospectivos , Transfecção
18.
BMC Cancer ; 16: 39, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26810856

RESUMO

BACKGROUND: Cancer metastasis is one of the most common causes of treatment failure and death in cancer patients. It has been acknowledged that aberrant activation of epithelial-to-mesenchymal transition (EMT) program, endows cancer cells with metastatic competence for which E-cadherin switch is a well-established hallmark. Suppression of E-cadherin by its transcriptional repressor Slug is thus a determining factor for EMT. Here, we aimed at discerning (i) the molecular mechanisms that regulate Slug/E-cadherin axis in oncogenic K-ras-expressing non-small cell lung carcinoma (NSCLC) cells, and (ii) the effect of aspirin in modulating the same. METHODS: The migratory behaviour of NSCLC cell line A549 were deciphered by wound healing assay. Further assessment of the molecular mechanisms was done by western blotting, RT-PCR, confocal microscopy, chromatin immunoprecipitation and small interfering RNA (siRNA)-mediated gene silencing. RESULTS: Here we report that in oncogenic K-ras-expressing A549 cells, Ras/ERK downstream Elk-1 forms p-Elk-1-p300 complex that being directly recruited to SLUG promoter acetylates the same to ensure p65NFκB binding for transcriptional up-regulation of Slug, a transcriptional repressor of E-cadherin. Aspirin inhibits EMT and decelerates the migratory potential of A549 cells by down-regulating Slug and thereby up-regulating E-cadherin. Aspirin impedes activation and nuclear translocation of p65NFκB, essential for this transcription factor being available for SLUG promoter binding. As a consequence, Slug transcription is down-regulated relieving A549 cells from Slug-mediated repression of E-cadherin transcription, thereby diminishing the metastatic potential of these oncogenic Ras-expressing NSCLC cells. CONCLUSIONS: Cumulatively, these results signify a crucial role of the anti-inflammatory agent aspirin as a novel negative regulator of epithelial-to-mesenchymal transition thereby suggesting its candidature as a promising tool for deterring metastasis of highly invasive K-ras-expressing NSCLC cells.


Assuntos
Aspirina/administração & dosagem , Caderinas/biossíntese , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Fatores de Transcrição/biossíntese , Caderinas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição da Família Snail , Fator de Transcrição RelA/biossíntese , Fator de Transcrição RelA/genética , Fatores de Transcrição/genética
19.
J Nanosci Nanotechnol ; 15(9): 6931-41, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26716265

RESUMO

A simple and cost-effective in-situ chemical route to prepare the nanocomposites based on graphene and Poly(aniline-co-pyrrole) [PPP] has been proposed. Introduction of graphene changes the morphology of copolymer from spherical to fiber like. Graphene/Poly(aniline-co-pyrrole) [GPPP] nanocomposite achieved highest specific capacitance of 351 F/g and energy density of 124.8 Wh/Kg at 10 mV/s scan rate. The composite also obtained moderate specific capacitance retention of 66% after 500 cycles, which establish its potentiality as supercapacitor electrode materials. The composite also exhibited high electrical conductivity and superior microwave absorbing properties (maximum reflection loss is -29.97 dB). The absorption range corresponding to ≥ 90% absorption (or -10 dB) is 2.72 GHz which is excellent for the microwave absorbing applications.

20.
PLoS One ; 10(7): e0134425, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26226135

RESUMO

Previously we demonstrated that human glioblastoma cell lines induce apoptosis in peripheral blood T cells through partial involvement of secreted gangliosides. Here we show that GBM-derived gangliosides induce apoptosis through involvement of the TNF receptor and activation of the caspase cascade. Culturing T lymphocytes with GBM cell line derived gangliosides (10-20 µg/ml) demonstrated increased ROS production as early as 18 hrs as indicated by increased uptake of the dye H2DCFDA while western blotting demonstrated mitochondrial damage as evident by cleavage of Bid to t-Bid and by the release of cytochrome-c into the cytosol. Within 48-72 hrs apoptosis was evident by nuclear blebbing, trypan blue positivity and annexinV/7AAD staining. GBM-ganglioside induced activation of the effector caspase-3 along with both initiator caspases (-9 and -8) in T cells while both the caspase-8 and -9 inhibitors were equally effective in blocking apoptosis (60% protection) confirming the role of caspases in the apoptotic process. Ganglioside-induced T cell apoptosis did not involve production of TNF-α since anti-human TNFα antibody was unable to protect T cells from nuclear blebbing and subsequent cell death. However, confocal microscopy demonstrated co-localization of GM2 ganglioside with the TNF receptor and co-immunoprecipitation experiments showed recruitment of death domains FADD and TRADD with the TNF receptor post ganglioside treatment, suggesting direct interaction of gangliosides with the TNF receptor. Further confirmation of the interaction between GM2 and TNFR1 was obtained from confocal microscopy data with wild type and TNFR1 KO (TALEN mediated) Jurkat cells, which clearly demonstrated co-localization of GM2 and TNFR1 in the wild type cells but not in the TNFR1 KO clones. Thus, GBM-ganglioside can mediate T cell apoptosis by interacting with the TNF receptor followed by activation of both the extrinsic and the intrinsic pathway of caspases.


Assuntos
Apoptose/fisiologia , Caspases/fisiologia , Gangliosídeo G(M2)/fisiologia , Glioblastoma/fisiopatologia , Transdução de Sinais/fisiologia , Linfócitos T/fisiologia , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Glioblastoma/metabolismo , Humanos , Imunoprecipitação , Células Jurkat/fisiologia , Microscopia Confocal , Espécies Reativas de Oxigênio/metabolismo , Receptores do Fator de Necrose Tumoral/fisiologia
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