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1.
Cancer Metastasis Rev ; 43(1): 261-292, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38169011

RESUMO

Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias , Humanos , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais , Adaptação Fisiológica , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
2.
Curr Med Chem ; 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38243984

RESUMO

The dreadful scenario of cancer prevails due to the presence of cancer stem cells (CSCs), which contribute to tumor growth, metastasis, invasion, resistance to chemo- and radiotherapy, and recurrence. CSCs are a small subpopulation of cells within the tumor that are characterized by self-renewal capability and have the potential to manifest heterogeneous lineages of cancer cells that constitute the tumor. The major bioactive green tea polyphenol (-)-epigallocatechin gallate (EGCG) has been fruitful in downgrading cancer stemness signaling and CSC biomarkers in cancer progression. EGCG has been evidenced to maneuver extrinsic and intrinsic apoptotic pathways in order to decrease the viability of CSCs. Cancer stemness is intricately related to epithelial-mesenchymal transition (EMT), metastasis and therapy resistance, and EGCG has been evidenced to regress all these CSC-related effects. By inhibiting CSC characteristics EGCG has also been evidenced to sensitize the tumor cells to radiotherapy and chemotherapy. However, the use of EGCG in in vitro and in vivo cancer models raises concern about its bioavailability, stability and efficacy against spheroids raised from parental cells. Therefore, novel nano formulations of EGCG and adjuvant therapy of EGCG with other phytochemicals or drugs or small molecules may have a better prospect in targeting CSCs. However, extensive clinical research is still awaited to elucidate a full proof impact of EGCG in cancer therapy.

3.
Biochim Biophys Acta Rev Cancer ; 1879(1): 189034, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38040268

RESUMO

The gene p63 has two isoforms -a full length transactivated isoform (TA) p63 and an amino-terminally truncated isoform, ∆Np63. DeltaNp63 alpha (∆Np63α) is the predominant splice variant of the isoform, ∆Np63 and is expressed in the basal layer of stratified epithelia. ∆Np63α that is normally essential for the epithelial lineage maintenance may be dysregulated in squamous cell carcinomas (SCCs). The pro-tumorigenic or antitumorigenic role of ∆Np63 is a highly contentious arena. ∆Np63α may act as a double-edged sword. It may either promote tumor progression, epithelial-mesenchymal transition, migration, chemoresistance, and immune-inflammatory responses, or inhibit the aforementioned phenomena depending upon cell type and tumor microenvironment. Several signaling pathways, transforming growth factor-ß, Wnt and Notch, as well as epigenetic alterations involving microRNAs, and long noncoding RNAs are regulated by ∆Np63α. This review has attempted to provide an in-depth insight into the role of ∆Np63α in the development of SCCs during different stages of tumor formation and how it may be targeted for therapeutic implications.


Assuntos
Carcinoma de Células Escamosas , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Isoformas de Proteínas/genética , Microambiente Tumoral
4.
Cancers (Basel) ; 15(15)2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37568796

RESUMO

Lung cancer is a heterogeneous group of malignancies with high incidence worldwide. It is the most frequently occurring cancer in men and the second most common in women. Due to its frequent diagnosis and variable response to treatment, lung cancer was reported as the top cause of cancer-related deaths worldwide in 2020. Many aberrant signaling cascades are implicated in the pathogenesis of lung cancer, including those involved in apoptosis (B cell lymphoma protein, Bcl-2-associated X protein, first apoptosis signal ligand), growth inhibition (tumor suppressor protein or gene and serine/threonine kinase 11), and growth promotion (epidermal growth factor receptor/proto-oncogenes/phosphatidylinositol-3 kinase). Accordingly, these pathways and their signaling molecules have become promising targets for chemopreventive and chemotherapeutic agents. Recent research provides compelling evidence for the use of plant-based compounds, known collectively as phytochemicals, as anticancer agents. This review discusses major contributing signaling pathways involved in the pathophysiology of lung cancer, as well as currently available treatments and prospective drug candidates. The anticancer potential of naturally occurring bioactive compounds in the context of lung cancer is also discussed, with critical analysis of their mechanistic actions presented by preclinical and clinical studies.

5.
Front Pharmacol ; 14: 1176819, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37305533

RESUMO

Constitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung adenocarcinoma (LUAD) may be counteracted by theaflavin-rich black tea (BT). A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT. BT-mediated NRF2 reorientation was observed to be dependent on concentration and duration of treatment as well as on the mutational profile of NRF2 in A549 cells. Transient exposure of low-concentration BT hormetically downregulated NRF2, its downstream antioxidants, and drug transporter. BT also influenced the Kelch-like ECH-associated protein (KEAP1)-dependent cullin 3 (Cul3) and KEAP-1-independent signaling through epidermal growth factor receptor (EGFR) - rat sarcoma virus (RAS) - rapidly accelerated fibrosarcoma (RAF) - extracellular signal-regulated kinase 1/2 (ERK) - matrix metalloproteinase (MMP)-2 and MMP-9. The realignment of NRF2 in KEAP1-suppressed A549 cells enhanced the chemotherapeutic outcome. But a higher concentration of the same BT surprisingly upregulated NRF2 and its transcriptional targets with a subsequent decrease in the NRF2-regulatory machinery in NCI-H23 cells (a KEAP1-overexpressed LUAD cell line), ultimately resulting in a better anticancer response. The BT-mediated bidirectional NRF2 modulation was reconfirmed upon comparison with the action of a pharmacological NRF2 inhibitor, ML-385, in A549 and a known NRF2 activator, tertiary-butylhydroquinone, in NCI-H23 respectively. BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level.

6.
Environ Sci Pollut Res Int ; 30(3): 7836-7850, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36044145

RESUMO

The metalloid arsenic (As) induces oxidative stress is a well-known fact. However, the extent of variation of oxidative stress according to different exposure levels of As in groundwater and the mechanism responsible for As mediated oxidative stress is yet to be elucidated in a human population of West Bengal. In the present study, we have investigated the impact of low level (> 10 ≤ 50 µg/L) and high-level groundwater As (> 50 µg/L) on cellular redox status, DNA damage, and repair mechanisms in chronically exposed rural women of West Bengal. Prediction models of ordinary least square regression of nail As, forced vital capacity (FVC) %, and that of forced expiratory volume during the first one second (FEV1) % deciphered that accumulation of As in nails may predict hemoglobin deficiency. Moreover, consumption of As-laced water tends to decrease FEV1% and FVC%. A strong positive correlation was observed between water and nail As level and reactive oxygen species (ROS) generation. ROS, perturbed nuclear factor erythroid 2-related factor 2(Nrf2)/ Kelch-like ECH-associated protein 1 (Keap1) redox regulation, compromised antioxidant defense machinery-superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione transferase (GST), induced DNA damage, and suppressed DNA repair proteins-poly ADP ribose polymerase1(PARP1)/ X-ray repair cross-complementing protein 1(XRCC1)/ 8-oxoguanine glycosylase (OGG1) in a dose-dependent manner. All the low and high As areas had very high cancer risk values for the exposed population. It has been predicted that if the As level in the drinking water of a 40-year adult increases by 2 ug/L, the likelihood of the cancer risk will increase by 10%, keeping the body weight and amount of water intake constant. Thus, long-term exposure to either low or high As is seriously affecting the lives of asymptomatic women who are vulnerable to developing carcinogenic changes after a period of latency.


Assuntos
Arsênio , Adulto , Humanos , Feminino , Espécies Reativas de Oxigênio/metabolismo , Arsênio/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Água/metabolismo , Homeostase , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
7.
Pharmacol Res ; 182: 106319, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35732198

RESUMO

Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2), the redox-sensitive transcription factor, plays a key role in stress-defense and detoxification. Nrf2 is tightly controlled by its negative regulator cum sensor Kelch-[ECH]-associated protein 1 (Keap1). Nrf2 is well known for its dual nature owing to its cancer preventive and cancer promoting abilities. Modulation of this biphasic nature of Nrf2 signaling by phytochemicals may be a potential cancer preventive and anticancer therapeutic strategy. Phytocompounds may either act as Nrf2-activator or Nrf2-inhibitor depending on their differential concentration and varied cellular environment. Tea is not just the most popular global beverage with innumerable health-benefits but has well-established chemopreventive and chemotherapeutic effects. Various types of tea infusions contain a wide range of bioactive compounds, such as polyphenolic catechins and flavonols, which are endowed with potent antioxidant properties. Despite of their rapid biotransformation and poor bioavailability, regular tea consumption is risk-reductive for several cancer forms. Tea catechins show their dual Nrf2-modulatory effect by directly acting on Nrf2-Keap1 or their upstream regulators and downstream effectors in a highly case-specific manner. In this review, we have tried to present a comprehensive evaluation of the Nrf2-mediated chemopreventive and chemotherapeutic applications of tea in various preclinical cancer models, the Nrf2-modulatory mechanisms, and the limitations which need to be addressed in future research.


Assuntos
Fator 2 Relacionado a NF-E2 , Neoplasias , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Chá
8.
J Biochem Mol Toxicol ; 36(4): e22999, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35218280

RESUMO

Pulmonary cancer confronts the greatest hurdle of resistance against most chemotherapeutic drugs. This may be circumvented with a combination of conventional chemotherapy with bioactive herbal adjuvant. Epigallocatechin-3-gallate (EGCG), was investigated for its chemo-sensitizing property along with doxorubicin (Dox), in an intrinsically nonresponsive lung adenocarcinoma (LAC) cell line, A549. A compromised functionality of Dox was reversed when EGCG was used as an adjuvant. On one hand, Dox (10 µM)-EGCG (0.5 µM) post treatment combination decreased the drug efflux, multidrug-resistance (MDR) signaling, invasiveness while, on the other hand, it increased drug internalization, cell-cycle arrest, stress-induced damage, and finally cell death. The resistant nature of A549 was probably due to constitutive activation of nuclear erythroid 2-related factor 2 (Nrf2) and its upstream/downstream antioxidant effectors, which were also pro-oxidatively coordinated by EGCG. In conclusion low dose EGCG improved Dox-toxicity and imparted oxidative damage-mediated antineoplastic efficacy by reorienting the redox signaling in A549 LAC cells.


Assuntos
Adenocarcinoma de Pulmão , Catequina , Neoplasias Pulmonares , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Doxorrubicina/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Oxirredução
9.
Fundam Clin Pharmacol ; 36(1): 49-71, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34655261

RESUMO

Propofol as an intravenous anesthetic and isoflurane as an inhalational/volatile anesthetic continue to be an important part of surgical anesthetic interventions worldwide. The impact of these anesthetics on tumor progression, immune modulation, and survival rates of cancer patients has been widely investigated. Although most of the preclinical studies have provided a beneficial effect of propofol over isoflurane or other volatile anesthetics, several investigations have shown contradictory results, which warrant more preclinical and clinical studies. Propofol mostly exhibits antitumor properties, whereas isoflurane being a cost-effective anesthetic is frequently used. However, isoflurane has been also reported with protumorigenic activity. This review provides an overall perspective on the network of signaling pathways that may modulate several steps of tumor progression from inflammation, immunomodulation, epithelial-mesenchymal transition (EMT) to invasion, metastasis, angiogenesis, and cancer stemness and extracellular vesicles along with chemotherapeutic applications and clinical status of these anesthetics. A clear understanding of the mechanistic viewpoints of these anesthetics may pave the way for more prospective clinical trials with the ultimate goal of obtaining a safe and optimal anesthetic intervention that would prevent cancer recurrence and may influence better postoperative survival.


Assuntos
Anestésicos Inalatórios , Isoflurano , Propofol , Humanos , Recidiva Local de Neoplasia , Propofol/farmacologia , Estudos Prospectivos
10.
Bioengineering (Basel) ; 8(10)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34677212

RESUMO

Extracellular nano vesicles and exosomes hold compelling evidence in intercellular communication. Exosomal intracellular signal transduction is mediated by the transfer of cargo proteins, lipids, micro (mi)RNAs, long noncoding (lnc)RNAs, small interfering (si)RNAs, DNA, and other functional molecules that play a pivotal role in regulating tumor growth and metastasis. However, emerging research trends indicate that exosomes may be used as a promising tool in anticancer treatment. This review features a majority of the bioengineering applications of fabricated exosomal cargoes. It also encompasses how the manipulation and delivery of specific cargoes-noncoding RNAs (ncRNAs), recombinant proteins, immune-modulators, chemotherapeutic drugs, and other small molecules-may serve as a precise therapeutic approach in cancer management.

11.
Cancers (Basel) ; 13(2)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477340

RESUMO

Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.

12.
Biomolecules ; 10(11)2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33207810

RESUMO

Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias/genética , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Animais , Variação Biológica da População/fisiologia , Carcinogênese/metabolismo , Progressão da Doença , Epigênese Genética/fisiologia , Humanos , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição
13.
Regul Toxicol Pharmacol ; 115: 104684, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32454235

RESUMO

The World Health Organization (WHO) recommended maximum contaminant level (MCL) of arsenic (As) in drinking water at 10 µg/L. Many Asian countries still have their MCL for As at 50 µg/L. The current cross sectional study was conducted on asymptomatic females (without As related skin lesions) selected from rural areas of West Bengal, Baruipur and Dhamakhali [low As 11-50 µg/L; N,93]; Kamardanga & Sibhati [high As>50 µg/L; N,70] and Boria [Control; As<10 µg/L N,118] of West Bengal, India. The study was designed to compare the status of peripheral blood and lung function due to prolonged As exposure. The lung function parameters were considered according to Miller's prediction quadrant - FVC less than 80% indicated restrictive lung, FEV1/FVC less than 70% showed obstructive lung and both FVC and FEV1/FVC less than predicted percentage exhibited combined lung function decrement. The study showed that groundwater As concentration [22.5 ± 19.2 (low), 67.8 ± 26.9 (high) and 1.02 ± 2.3 µg/L (control)] was correlated with nail As content of the enrolled women. Linear regression depicted that nail As content influenced reduction of haemoglobin (ß: 0.43; 95%CI: 0.02 to -0.006; p = 0.0001) and CD56+ NK cells (ß: 0.53; 95%CI: 0.07 to -0.03; p = 0.0001) per 1 µg/g increase in As in nails. Multivariate logistic regression exhibited that nail As content was associated with reduction of lung function parameters [FEV1 (Exp B:1.04; 95%CI: 1.022 to 1.055; p = 0.0001) and FVC (Exp B:1.05; 95%CI: 1.03 to 1.07; p = 0.0001) per 1 µg/g increase in As in nails. Hence the study may be indicative of the fact that even in asymptomatic women, increase in chronic As exposure may weaken immune surveillance and provoke respiratory ailments.


Assuntos
Arsênio/toxicidade , Células Matadoras Naturais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Adulto , Arsênio/análise , Água Potável , Feminino , Volume Expiratório Forçado , Água Subterrânea/análise , Hemoglobinas/análise , Humanos , Índia , Pulmão/fisiologia , Pessoa de Meia-Idade , Unhas/química , Testes de Função Respiratória , População Rural , Capacidade Vital , Poluentes Químicos da Água/análise
14.
J Appl Toxicol ; 40(1): 87-131, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31273810

RESUMO

Groundwater arsenic (As) contamination is a global public health concern. The high level of As exposure (100-1000 µg/L or even higher) through groundwater has been frequently associated with serious public health hazards, e.g., skin disorders, cardiovascular diseases, respiratory problems, complications of gastrointestinal tract, liver and splenic ailments, kidney and bladder disorders, reproductive failure, neurotoxicity and cancer. However, reviews on low-level As exposure and the imperative health effects are far less documented. The World Health Organization (WHO) and the United States Environmental Protection Agency (USEPA) has set the permissible standard of As in drinking water at 10 µg/L. Considering the WHO and USEPA guidelines, most of the developed countries have established standards at or below this guideline. Worldwide many countries including India have millions of aquifers with low-level As contamination (≤50 µg/L). The exposed population of these areas might not show any As-related skin lesions (hallmark of As toxicity particularly in a population consuming As contaminated groundwater >300 µg/L) but might be subclinically affected. This review has attempted to encompass the wide range of health effects associated with chronic low-level As exposure ≤50 µg/L and the probable mechanisms that might provide a better insight regarding the underlying cause of these clinical manifestations. Therefore, there is an urgent need to create mass awareness about the health effects of chronic low-level As exposure and planning of proper mitigation strategies.


Assuntos
Intoxicação por Arsênico/epidemiologia , Arsênio/efeitos adversos , Exposição Ambiental/efeitos adversos , Saúde Global , Água Subterrânea/análise , Saúde Pública , Poluentes Químicos da Água/efeitos adversos , Arsênio/análise , Intoxicação por Arsênico/diagnóstico , Monitoramento Ambiental , Nível de Saúde , Humanos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Poluentes Químicos da Água/análise
15.
Antioxid Redox Signal ; 33(17): 1230-1256, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31813247

RESUMO

Significance: Phytochemicals are important dietary constituents with antioxidant properties. They affect various signaling pathways involved in the overall maintenance of interior milieu of the cell. Arsenic, an environmental toxicant, is well known for its deleterious consequences, such as various diseases, including cancers in humans. Mitochondria are the cell's powerhouse that fuel all metabolic energy requirements. Dysfunctional mitochondria due to stressors may lead to abnormal functioning of the organelle, hampering the crucial cellular cross talks and ultimately leading to cancer. Application of phytochemicals against arsenic-induced mitochondrial disorders may be a preventive measure to counteract the ruinous impacts of the metalloid. Recent Advances: In recent years, extensive research on the role of mitochondria in cancer gives a better understanding of the areas the organelle covers in maintaining a healthy cell or in inducing carcinogenicity. Detailed knowledge of the mitochondrial governances would enable researchers to administer numerous phytochemicals to ameliorate altered oxidative phosphorylation, mitochondrial membrane potential (MMP), mitochondrial oxidative stress, unfolded protein response, glycolysis, or even apoptosis. Critical Issues: In this review, we have addressed how various phytochemicals belonging to diverse classes combat against arsenic-induced mitochondrial oxidative stress, depletion of MMP, cell cycle abrogation, apoptosis, glycolytic damages, oncogenic regulations, chaperones, mitochondrial complexes, and mitochondrial membrane pore formation in both in vitro and in vivo models. Future Directions: Insightful application of mitoprotective phytochemicals against arsenic-induced mitochondrial oxidative stress and carcinogenesis may guide researchers to develop preclinical chemopreventive agents to fight arsenic toxicity in humans.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Arsênio/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Compostos Fitoquímicos/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Animais , Ciclo Celular , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/patologia
16.
Int J Mol Sci ; 20(3)2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30708951

RESUMO

Malignant melanoma is a highly aggressive form of skin cancer which has a propensity for metastasis. Epithelial mesenchymal transition (EMT) plays a primordial role in the progression of metastatic disease. Metastatic melanoma is resistant to conventional therapies. Hence, researchers have been exploring alternative approaches, including the utility of bioactive phytochemicals to manage metastatic disease. In the present study, we investigated the potential of cirsiliol, a flavonoid isolated from Centaurea jacea L., in modulating the aggressive behavior of B16F10 metastatic melanoma cells, including EMT, and associated molecular mechanisms of action. Cirsiliol was found to be effective in restraining the colony formation and migration of fibronectin-induced B16F10 metastatic melanoma cells. Cirsiliol inhibited the activity and expression of matrix metalloproteinase-9 (MMP-9). Cirsiliol also suppressed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (also known as Akt)/nuclear factor-κB (NF-κB) signaling pathway which, in turn, caused upregulation of E-cadherin and downregulation of N-cadherin, Snail and Twist. Based on these results, cirsiliol may be considered a promising compound against EMT in the therapeutic management of malignant melanoma.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Flavonas/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Flavonas/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma Experimental/metabolismo , Camundongos , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Cutâneas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Semin Cancer Biol ; 56: 196-218, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30472212

RESUMO

Epithelial to mesenchymal transition (EMT) is a biological phenomenon that plays a primordial role for initiation of metastasis. It renders cancer cells with increased self-renewal and tumor-initiating capabilities and exacerbated resistance to apoptosis and chemotherapy. Hence, regulation of EMT stands out to be an important strategy in controlling the behavior of malignant cells. Despite the enormous amount of preclinical data on the implication of EMT in cancer progression, there is still lack of routine clinical translation at therapeutic levels. The need of EMT-modulating drugs with high efficacy and low cytotoxicity has led to studies involving the evaluation of the efficacy of a plethora of various classes of phytochemicals present in dietary sources of fruits and vegetables. This review summarizes the role of these different classes of phytochemicals, their natural/synthetic analogs, and their nano-formulations in regulation of EMT in various preclinical models through attenuation of primary signaling pathways. Numerous proteins, transcription factors and enzymes targeted by various classes of phytochemicals in repression of EMT has been presented in this review. Additionally, we have critically analyzed the existing literature and provided views on new direction for accelerating the discovery of novel drug candidates which could be cautiously administered without concomitant effects.


Assuntos
Suplementos Nutricionais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Biomarcadores , Quimioprevenção , Epigênese Genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Compostos Fitoquímicos/química , Transdução de Sinais/efeitos dos fármacos
18.
Food Funct ; 10(1): 191-202, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30516195

RESUMO

Globally, non-small cell lung cancer is a leading cause of cancer-related mortality and about 40% of these cancers are detected in the metastatic stage. Epithelial mesenchymal transition (EMT) plays a critical role during malignant transformation, and the extracellular matrix component, fibronectin (FN), is a known inducer of invasion and metastasis. Diallyl disulphide (DADS), a bioactive component of garlic, exhibits a wide spectrum of biological activities including the inhibition of cancer cell migration and invasion. The present study was aimed at deciphering the effect of DADS on the regulation of FN-induced EMT in A549 lung cancer cells. DADS suppressed the FN-induced invasion and migration potential of A549 cells which may be attributed to the reduced activity of gelatinases. DADS suppressed the FN-aggravated EMT of A549 cells by the upregulation of the epithelial markers, E-cadherin and cytokeratin-18, and the downregulation of the mesenchymal markers, N-cadherin and vimentin, and the transcription factors, snail, slug and twist. DADS was effective in inhibiting the nuclear translocation of ß-catenin and the phosphorylation of glycogen synthase kinase-3ß and in suppressing the activity of dishevelled homolog 2 and T-cell-factor/lymphoid enhancer factor in FN-induced A549 cells. Cumulatively, this study indicated that DADS might be able to reverse FN-induced EMT in A549 cells via the suppression of Wnt signaling.


Assuntos
Compostos Alílicos/farmacologia , Dissulfetos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibronectinas/metabolismo , Neoplasias Pulmonares/fisiopatologia , Via de Sinalização Wnt/efeitos dos fármacos , Células A549 , Caderinas/genética , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Humanos , Queratina-18/genética , Queratina-18/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
19.
J Appl Toxicol ; 38(8): 1071-1080, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29572906

RESUMO

Arsenite (AsIII) is known for inducing severe oxidative stress and skin carcinogenesis. Contrastingly, phytochemical, epigallocatechin-3-gallate (EGCG) combats toxic insults. Our study focused on the effect of EGCG on redox status of AsIII-stressed normal human keratinocytes, HaCaT cells. EGCG (50 µm) increased the cell viability by 29% in AsIII (50 µm) insulted HaCaT cells but exhibited pro-oxidant activity by elevated expression of the oxidative stress markers. EGCG was effective not only in reducing AsIII-induced nuclear expression of Nrf2 and Nrf2Ser40 but also in increasing nuclear expression of Keap1 both at protein and mRNA level. EGCG did not have similar effects on all Nrf2 downstream targets. EGCG elevated expression of HO-1 and γ-GCL,showed no change in MRP1 but decreased superoxide dismutase, NAD(P)H dehydrogenase quinone 1 and glutathione S transferase activity in AsIII-treated HaCaT cells. EGCG along with AsIII caused decreased phosphorylation of Nrf2 at ser40 residue, which might have facilitated Keap1-mediated nuclear export and degradation of Nrf2 and paved the pro-survival signal for AsIII-insulted HaCaT cells. In conclusion, it might be indicated that EGCG in spite of inducing the pro-oxidant effect was effective in increasing the viability of AsIII-treated HaCaT cells by partially restoring the Nrf2/Keap1-mediated signaling axis.


Assuntos
Arsenitos/toxicidade , Catequina/análogos & derivados , Homeostase/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/metabolismo , Catequina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
20.
Semin Cancer Biol ; 46: 33-54, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28396252

RESUMO

The National Cancer Institute of the United States had projected breast cancer as one of the topmost prevalent malignancies of 2016. It was estimated that in 2016, 246,660 new cases of invasive breast cancer were expected to be diagnosed in women in the US, along with 61,000 new cases of non-invasive (in situ) breast cancer. The heterogeneity of breast cancer accounts for its differential molecular subtyping. Recent incorporation of high throughput approaches helps early prognosis of breast cancer, but recurrence of the disease stands to be one of the most daunting fact behind non-availability of third line treatment. At this point of crisis, application of chemopreventive measures could possibly resolve the enigma of breast cancer. The world class beverage tea has proven its efficacy in ameliorating various genetic and epigenetic anomalies in breast cancer. Tea phytoconstituents are known to modulate myriad molecular events which include prominent regulators of intracellular signaling, such as phosphatidylinositide 3-kinase/protein kinase B/nuclear factor-κB, epidermal growth factor receptor, vascular endothelial growth factor, B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein in the development and progression of breast carcinoma. This review aims to encompass the detailed modulatory roles of tea phytochemicals, their analogs and nanoformulations against mammary carcinoma and the probability of using tea in therapeutic management of breast cancer. Finally, current limitations, challenges and future directions of tea and breast cancer research are also critically discussed.


Assuntos
Neoplasias da Mama/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Chá/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/dietoterapia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Compostos Fitoquímicos/química
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