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1.
Sensors (Basel) ; 24(14)2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39065965

RESUMEN

This paper presents a control strategy synthesis method for dynamical systems with differential constraints, emphasizing the prioritization of specific rules. Special attention is given to scenarios where not all rules can be simultaneously satisfied to complete a given task, necessitating decisions on the extent to which each rule is satisfied, including which rules must be upheld or disregarded. We propose a learning-based Model Predictive Control (MPC) method designed to address these challenges. Our approach integrates a learning method with a traditional control scheme, enabling the controller to emulate human expert behavior. Rules are represented as Signal Temporal Logic (STL) formulas. A robustness margin, quantifying the degree of rule satisfaction, is learned from expert demonstrations using a Conditional Variational Autoencoder (CVAE). This learned margin is then applied in the MPC process to guide the prioritization or exclusion of rules. In a track driving simulation, our method demonstrates the ability to generate behavior resembling that of human experts and effectively manage rule-based dilemmas.

2.
Medicines (Basel) ; 11(3)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38535120

RESUMEN

Background: This study investigated how the expression of heat shock protein 27 (HSP27), cellular FLICE-like inhibitory protein (cFLIP), and clusterin (CLU) affects the progression of cancer cells and their susceptibility to doxazosin-induced apoptosis. By silencing each of these genes individually, their effect on prostate cancer cell viability after doxazosin treatment was investigated. Methods: PC-3 prostate cancer cells were cultured and then subjected to gene silencing using siRNA targeting HSP27, cFLIP, and CLU, either individually, in pairs, or all together. Cells were then treated with doxazosin at various concentrations and their viability was assessed by MTT assay. Results: The study found that silencing the CLU gene in PC-3 cells significantly reduced cell viability after treatment with 25 µM doxazosin. In addition, the dual silencing of cFLIP and CLU decreased cell viability at 10 µM doxazosin. Notably, silencing all three genes of HSP27, cFLIP, CLU was most effective and reduced cell viability even at a lower doxazosin concentration of 1 µM. Conclusions: Taken together, these findings suggest that the simultaneous silencing of HSP27, cFLIP, and CLU genes may be a potential strategy to promote apoptosis in prostate cancer cells, which could inform future research on treatments for malignant prostate cancer.

3.
Bioorg Chem ; 143: 107061, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38154386

RESUMEN

Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC50 value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI50 values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the ß-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the ß-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.


Asunto(s)
Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Proteína Glutamina Gamma Glutamiltransferasa 2 , Animales , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Imidazoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Simulación del Acoplamiento Molecular , Proteína Glutamina Gamma Glutamiltransferasa 2/antagonistas & inhibidores , Transglutaminasas/antagonistas & inhibidores , Transglutaminasas/metabolismo , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo
4.
Adv Sci (Weinh) ; 10(12): e2206800, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36808490

RESUMEN

Spin current, converted from charge current via spin Hall or Rashba effects, can transfer its angular momentum to local moments in a ferromagnetic layer. In this regard, the high charge-to-spin conversion efficiency is required for magnetization manipulation for developing future memory or logic devices including magnetic random-access memory. Here, the bulk Rashba-type charge-to-spin conversion is demonstrated in an artificial superlattice without centrosymmetry. The charge-to-spin conversion in [Pt/Co/W] superlattice with sub-nm scale thickness shows strong W thickness dependence. When the W thickness becomes 0.6 nm, the observed field-like torque efficiency is about 0.6, which is an order larger than other metallic heterostructures. First-principles calculation suggests that such large field-like torque arises from bulk-type Rashba effect due to the vertically broken inversion symmetry inherent from W layers. The result implies that the spin splitting in a band of such an ABC-type artificial SL can be an additional degree of freedom for the large charge-to-spin conversion.

5.
Nature ; 612(7940): 470-476, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36517715

RESUMEN

Quantitative determination and in situ monitoring of molecular chirality at extremely low concentrations is still challenging with simple optics because of the molecular-scale mismatch with the incident light wavelength. Advances in spectroscopy1-4 and nanophotonics have successfully lowered the detection limit in enantioselective sensing, as it can bring the microscopic chiral characteristics of molecules into the macroscopic scale5-7 or squeeze the chiral light into the subwavelength scale8-17. Conventional nanophotonic approaches depend mainly on the optical helicity density8,9 by localized resonances within an individual structure, such as localized surface plasmon resonances (LSPRs)10-16 or dielectric Mie resonances17. These approaches use the local chiral hotspots in the immediate vicinity of the structure, whereas the handedness of these hotspots varies spatially. As such, these localized resonance modes tend to be error-prone to the stochasticity of the target molecular orientations, vibrations and local concentrations18,19. Here we identified enantioselective characteristics of collective resonances (CRs)20 arising from assembled 2D crystals of isotropic, 432-symmetric chiral gold nanoparticles (helicoids)21,22. The CRs exhibit a strong and uniform chiral near field over a large volume above the 2D crystal plane, resulting from the collectively spinning, optically induced dipoles at each helicoid. Thus, energy redistribution by molecular back action on the chiral near field shifts the CRs in opposite directions, depending on the handedness of the analyte, maximizing the modulation of the collective circular dichroism (CD).

6.
Phytother Res ; 36(7): 2999-3008, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35634973

RESUMEN

The goal of the current study is to assess the antitumor mechanism by the combination (7:3) of Angelica gigas and Torilis japonica (AT) that was found most effective through screening against prostate-specific antigen (PSA) in LNCaP prostate cancer cells. Here, AT reduced the viability and the number of colonies in androgen-dependent LNCaP cells more than in androgen independent PC3 and DU145 cells. Also, AT induced G1 phase arrest, cleaved PARP and caspase 3, activated p27 and decreased the expression of Cyclin D1, Cyclin E, cdk2 in LNCaP cells. Furthermore, AT decreased the expression of PSA and androgen receptor (AR) at mRNA and protein levels in LNCaP cells. Interestingly, AT attenuated the expression of AR, PSA and Wnt-3a and the stability of AR and PSA in LNCaP cells. Furthermore, AT reversed dihydrotestosterone (DHT)-induced upregulation of AR and PSA in LnCaP cells. Notably, AT disrupted the protein-protein interaction, nuclear translocation and fluorescent expression of ß-catenin and AR in LNCaP cells. Consistently, ß-catenin depletion enhanced the decreased expression of AR in AT treated LNCaP cells. Taken together, our findings highlight evidence that AT suppresses the proliferation of LNCaP cells via G1 arrest and inhibition of ß-catenin and AR as a potential anticancer agent.


Asunto(s)
Angelica , Antineoplásicos Fitogénicos , Apiaceae , Preparaciones de Plantas , Neoplasias de la Próstata , Andrógenos , Angelica/química , Antineoplásicos Fitogénicos/farmacología , Apiaceae/química , Línea Celular Tumoral , Fase G1 , Humanos , Masculino , Preparaciones de Plantas/farmacología , Antígeno Prostático Específico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Vía de Señalización Wnt , beta Catenina
7.
Cells ; 11(8)2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35456022

RESUMEN

Herein, the apoptotic mechanism of 1,2,3,4,6-penta-O-galloyl-ß-D-glucopyranose (PGG) was examined in cisplatin-resistant lung cancer cells. PGG significantly reduced viability; increased sub-G1 accumulation and the number of terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL)-positive cells; induced the cleavage of poly (ADP-ribose) polymerase (PARP), caspases (8,9,3,7), B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN); and attenuated the expression of p-AKT, X-linked inhibitor of apoptosis protein (XIAP), Bcl-2, Bcl-xL and survivin in A549/cisplatin-resistant (CR) and H460/CR cells. Notably, PGG activated p53, p-checkpoint kinase 2 (CHK2) and p-H2A histone family member X (p-H2AX), with increased levels of DNA damage (DSBs) evaluated by highly expressed pH2AX and DNA fragmentation registered on comet assay, while p53 knockdown reduced the ability of PGG to reduce viability and cleave caspase 3 and PARP in A549/CR and H460/CR cells. Additionally, PGG treatment suppressed the growth of H460/CR cells in Balb/c athymic nude mice with increased caspase 3 expression compared with the cisplatin group. Overall, PGG induces apoptosis in cisplatin-resistant lung cancer cells via the upregulation of DNA damage proteins such as γ-H2AX, pCHK2 and p53.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Cisplatino , Neoplasias Pulmonares , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Caspasa 3/metabolismo , Línea Celular Tumoral , Quinasa de Punto de Control 2/metabolismo , Cisplatino/farmacología , Daño del ADN , Resistencia a Antineoplásicos , Glucosa , Humanos , Taninos Hidrolizables , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Fosforilación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo
8.
Semin Cancer Biol ; 86(Pt 3): 1033-1057, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-33301862

RESUMEN

Immune checkpoint proteins including programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are involved in proliferation, angiogenesis, metastasis, chemoresistance via immune escape and immune tolerance by disturbing cytotoxic T cell activation. Though many clinical trials have been completed in several cancers by using immune checkpoint inhibitors alone or in combination with other agents to date, recently multi-target therapy is considered more attractive than monotherapy, since immune checkpoint proteins work with other components such as surrounding blood vessels, dendritic cells, fibroblasts, macrophages, platelets and extracellular matrix within tumor microenvironment. Thus, in the current review, we look back on research history of immune checkpoint proteins and discuss their associations with platelets or tumor cell induced platelet aggregation (TCIPA) and FOXP3+ regulatory T cells (Tregs) related molecules involved in immune evasion and tumor progression, clinical implications of completed trial results and signaling networks by phytochemicals for combination therapy with immune checkpoint inhibitors and suggest future research perspectives.


Asunto(s)
Antígeno B7-H1 , Neoplasias , Humanos , Receptor de Muerte Celular Programada 1 , Plaquetas/metabolismo , Proteínas de Punto de Control Inmunitario , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Factores de Transcripción Forkhead , Microambiente Tumoral
9.
Semin Cancer Biol ; 86(Pt 2): 1066-1075, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-34428551

RESUMEN

Since cancer immunotherapy with immune checkpoint inhibitors of PD/PDL-1 and CTLA-4 limited efficacy to the patients due to resistance during the current decade, novel target is required for customized treatment due to tumor heterogeneity. V-domain Ig-containing suppressor of T cell activation (VISTA), a programmed death protein-1(PD-1) homolog expressed on T cells and on antigen presenting cells(APC), has emerged as a new target in several cancers. Though VISTA inhibitors including CA-170 are considered attractive in cancer immunotherapy to date, the information on VISTA as a potent biomarker of cancer prognosis and its combination therapy is still lacking to date. Thus, in this review, we discussed extracellular domain, ligands, expression, immune functions and clinical implications of VISTA and finally suggested conclusion and perspectives.


Asunto(s)
Inmunoterapia , Neoplasias , Humanos , Ligandos , Activación de Linfocitos , Neoplasias/terapia , Neoplasias/patología , Pronóstico
10.
Phytother Res ; 35(12): 6944-6953, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34709688

RESUMEN

Herein, apoptotic mechanism of Moracin D was explored in prostate cancer cells in association with peroxisome proliferator-activated receptor gamma (PPAR-γ)-related signaling involved in lipid metabolism. Moracin D augmented cytotoxicity and sub G1 population in PC3 and DU145 prostate cancer cells, while DU145 cells were more susceptible to Moracin D than PC3 cells. Moracin D attenuated the expression of caspase-3, poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2), and B-cell lymphoma-extra-large (Bcl-xL) in DU145 cells. Consistently, Moracin D significantly augmented the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in DU145 cells. Interestingly, Moracin D activated PPAR-γ and phospho-protein kinase C delta (p-PKC-δ) and inhibited phospho-protein kinase C alpha (p-PKC-α) in DU145 cells. Furthermore, STRING bioinformatic analysis reveals that PPAR-γ interacts with nuclear factor-κB (NF-κB) that binds to PKC-α/PKC-δ or protein kinase B (AKT) or extracellular signal-regulated kinase (ERK). Indeed, Moracin D decreased phosphorylation of NF-κB, ERK, and AKT in DU145 cells. Conversely, PPAR-γ inhibitor GW9662 reduced the apoptotic ability of Moracin D to activate caspase 3 and PARP in DU145 cells. Taken together, these findings provide a novel insight that activation of PPAR-γ/p-PKC-δ and inhibition of p-PKC-α are critically involved in Moracin D-induced apoptosis in DU145 prostate cancer cells.


Asunto(s)
Benzofuranos/farmacología , PPAR gamma , Neoplasias de la Próstata , Proteína Quinasa C-alfa , Proteína Quinasa C-delta , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Proteína Quinasa C-delta/antagonistas & inhibidores
11.
Cancers (Basel) ; 13(19)2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34638383

RESUMEN

Though UBE2M, an E2 NEDD8-conjugating enzyme, is overexpressed in HepG2, Hep3B, Huh7 and PLC/PRF5 HCCs with poor prognosis by human tissue array and TCGA analysis, its underlying oncogenic mechanism remains unclear. Herein, UBE2M depletion suppressed viability and proliferation and induced cell cycle arrest and apoptosis via cleavages of PARP and caspase 3 and upregulation of p53, Bax and PUMA in HepG2, Huh7 and Hep3B cells. Furthermore, UBE2M depletion activated p53 expression and stability, while the ectopic expression of UBE2M disturbed p53 activation and enhanced degradation of exogenous p53 mediated by MDM2 in HepG2 cells. Interestingly, UBE2M binds to MDM2 or ribosomal protein L11, but not p53 in HepG2 cells, despite crosstalk between p53 and UBE2M. Consistently, the colocalization between UBE2M and MDM2 was observed by immunofluorescence. Notably, L11 was required in p53 activation by UBE2M depletion. Furthermore, UBE2M depletion retarded the growth of HepG2 cells in athymic nude mice along with elevated p53. Overall, these findings suggest that UBE2M promotes cancer progression as a p53 negative regulator by binding to MDM2 and ribosomal protein L11 in HCCs.

12.
Int J Mol Sci ; 22(19)2021 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-34638959

RESUMEN

Though Morusin isolated from the root of Morus alba was known to have antioxidant, anti-inflammatory, antiangiogenic, antimigratory, and apoptotic effects, the underlying antitumor effect of Morusin is not fully understood on the glycolysis of liver cancers. Hence, in the current study, the antitumor mechanism of Morusin was explored in Hep3B and Huh7 hepatocellular carcninomas (HCC) in association with glycolysis and G1 arrest. Herein, Morusin significantly reduced the viability and the number of colonies in Hep3B and Huh7 cells. Moreover, Morusin significantly increased G1 arrest, attenuated the expression of cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) and upregulated p21 and p27 in Hep3B and Huh7 cells. Interestingly, Morusin significantly activated phosphorylation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) but attenuated the expression of the p-mammalian target of protein kinase B (AKT), rapamycin (mTOR), c-Myc, hexokinase 2(HK2), pyruvate kinases type M2 (PKM2), and lactate dehydrogenase (LDH) in Hep3B and Huh7 cells. Consistently, Morusin suppressed lactate, glucose, and adenosine triphosphate (ATP) in Hep3B and Huh7 cells. Conversely, the AMPK inhibitor compound C reduced the ability of Morusin to activate AMPK and attenuate the expression of p-mTOR, HK2, PKM2, and LDH-A and suppressed G1 arrest induced by Morusin in Hep3B cells. Overall, these findings suggest that Morusin exerts an antitumor effect in HCCs via AMPK mediated G1 arrest and antiglycolysis as a potent dietary anticancer candidate.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos/farmacología , Carcinoma Hepatocelular/metabolismo , Flavonoides/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Glucólisis/efectos de los fármacos , Neoplasias Hepáticas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Extractos Vegetales/farmacología , Carcinoma Hepatocelular/patología , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Hexoquinasa/metabolismo , Humanos , Lactato Deshidrogenasa 5/metabolismo , Neoplasias Hepáticas/patología , Proteínas de la Membrana/metabolismo , Morus/química , Raíces de Plantas/química , Serina-Treonina Quinasas TOR/metabolismo , Hormonas Tiroideas/metabolismo , Proteínas de Unión a Hormona Tiroide
13.
Cells ; 10(8)2021 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-34440834

RESUMEN

Novel target therapy is on the spotlight for effective cancer therapy. Hence, in the present study, the underlying apoptotic mechanism of Morusin was explored in association with miR193a-5p mediated ZNF746/c-Myc signaling axis in colorectal cancer cells (CRCs). Herein, Morusin reduced the viability and the number of colonies in HCT116 and SW480 CRCs. Additionally, Morusin increased sub-G1 population, cleavages of poly (ADP-ribose) polymerase (PARP) and caspase-3 and inhibited the expression of zinc finger protein 746 (ZNF746) and c-Myc in HCT116 and SW480 cells. Conversely, overexpression of ZNF746 suppressed the ability of Morusin to abrogate the expression of c-Myc in HCT116 cells, as ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization in HCT116 cells by immunofluorescence and immunoprecipitation. Notably, Morusin upregulated miR193a-5p as a tumor suppressor, while miR193a-5p inhibitor masked the ability of Morusin to reduce the expression of ZNF746, c-Myc, and pro-PARP in HCT116 cells. To our knowledge, these findings provide the novel insight on miR193a-5p mediated inhibition of ZNF746/c-Myc signaling in Morusin induced apoptosis in CRCs.


Asunto(s)
Apoptosis/efectos de los fármacos , Flavonoides/farmacología , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Represoras/metabolismo , Regiones no Traducidas 3' , Antagomirs/metabolismo , Secuencia de Bases , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Regulación hacia Abajo/efectos de los fármacos , Flavonoides/química , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Unión Proteica , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Represoras/química , Proteínas Represoras/genética , Alineación de Secuencia , Transducción de Señal , Regulación hacia Arriba/efectos de los fármacos
14.
Cells ; 10(8)2021 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-34440920

RESUMEN

Since the signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) signaling plays an important role in tumor-immune microenvironments, in the present study, the role of STAT3/PD-L1 signaling in the apoptotic mechanism of an active ginseng saponin metabolite compound K (CK) was investigated in human prostate cancer cells. Here, CK exerted significant cytotoxicity without hurting RWPE1 normal prostate epithelial cells, increased sub-G1 and cleavage of Poly ADP-ribose polymerase (PARP) and attenuated the expression of pro-PARP and Pro-cysteine aspartyl-specific protease3 (pro-caspase-3) in LANCap, PC-3 and DU145 cells. Further, CK attenuated the expression of p-STAT3 and PD-L1 in DU145 cells along with disrupted the binding of STAT3 to PD-L1. Furthermore, CK effectively abrogated the expression of p-STAT3 and PD-L1 in interferon-gamma (INF-γ)-stimulated DU145cells. Additionally, CK suppressed the expression of vascular endothelial growth factor (VEGF), transforming growth factor-ß (TGF-ß), interleukin 6 (IL-6) and interleukin 10 (IL-10) as immune escape-related genes in DU145 cells. Likewise, as STAT3 targets genes, the expression of CyclinD1, c-Myc and B-cell lymphoma-extra-large (Bcl-xL) was attenuated in CK-treated DU145 cells. Notably, CK upregulated the expression of microRNA193a-5p (miR193a-5p) in DU145 cells. Consistently, miR193a-5p mimic suppressed p-STAT3, PD-L1 and pro-PARP, while miR193a-5p inhibitor reversed the ability of CK to attenuate the expression of p-STAT3, PD-L1 and pro-PARP in DU145 cells. Taken together, these findings support evidence that CK induces apoptosis via the activation of miR193a-5p and inhibition of PD-L1 and STAT3 signaling in prostate cancer cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Antígeno B7-H1/metabolismo , Ginsenósidos/farmacología , MicroARNs/genética , Neoplasias de la Próstata/genética , Factor de Transcripción STAT3/metabolismo , Apoptosis/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Citocinas/genética , Citocinas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ginsenósidos/química , Humanos , Masculino , Estructura Molecular , Células PC-3 , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de los fármacos
15.
Phytother Res ; 35(8): 4547-4554, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34132431

RESUMEN

In the current study, the pivotal roles of serum and glucocorticoid-induced protein kinase (SGK1) and NF-kB related signalings known as prognostic biomarkers in cervical cancers were explored in the antitumor effect of a ginseng saponin metabolite compound K (CK) in HeLa and SiHa cervical cancer cells. CK exerted significant cytotoxicity, induced sub-G1 accumulation, and attenuated the expression of proPoly (ADP-ribose) polymerase (pro-PARP) and Pro-cysteine aspartyl-specific protease (pro-caspase3) in HeLa cells more than in SiHa cells. CK inhibited phosphorylation of SGK1 and its upstream genes, phosphoinositide 3-kinases (PI3K), and phosphoinositide-dependent kinase-1 (PDK1) in HeLa cells. In addition, CK suppressed the phosphorylation of SGK1, NF-κB, and inhibitor of kappa B (IκB) and also NF-κB target genes such as X-linked inhibitor of apoptosis protein and B-cell lymphoma 2 (Bcl-2) in HeLa cells. Notably, Immunoprecipitation revealed that SGK1 binds to PI3K or PDK1 and also CK disturbed the binding between SGK1 and PI3K or PDK1 in HeLa cells. Furthermore, PI3K inhibitor LY294002 decreased expression of PI3K, p-PDK1, p-SGK1, and pro-caspase3 and SGK1 inhibitor GSK650394 also reduced expression of NF-κB and pro-caspase3 just like CK in HeLa cells. Overall, these findings suggest that CK induces apoptosis via suppression of PI3K/PDK1/SGK1 and NF-κB signaling axis.


Asunto(s)
Ginsenósidos/farmacología , Proteínas Inmediatas-Precoces/metabolismo , Fosfatidilinositol 3-Quinasas , Proteínas Serina-Treonina Quinasas/metabolismo , Células HeLa , Humanos , Quinasa I-kappa B/metabolismo , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Quinasas , Transducción de Señal
16.
Phytother Res ; 35(8): 4538-4546, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34114707

RESUMEN

In the current study, the underlying anti-metastatic mechanism of melatonin contained in some edible plants was explored in association with transmembrane protease serine 4 (TMPRSS4) mediated metastasis and epithelial-mesenchymal transition (EMT) signaling in human HCT15 and SW620 colorectal cancer cells. Here, TMPRSS4 was highly expressed in HCT15, but was weakly expressed in SW620 cells. Melatonin exerted weak cytotoxicity, decreased invasion, adhesion, and migration, and attenuated the expression of TMPRSS4, cyclin E, pro-urokinase-type plasminogen activator (pro-uPA), p-signal transducer and activator of transcription 3 (p-STAT3), p-focal adhesion kinase (p-FAK), Snail and increased the expression of E-cadherin, p27, pp38 and p-Jun N-terminal kinases (p-JNK) in HCT15 cells. Conversely, overexpression of TMPRSS4 reduced the ability of melatonin to activate E-cadherin and reduce Snail. Furthermore, even in SW620 cells transfected with TMPRSS4-overexpression plasmid, melatonin effectively suppressed invasion and migration along with decreased expression of Snail, cyclin A, cyclin E, pro-uPA and p-FAK and increased expression of E-cadherin and p27. Overall, these findings provide evidence that melatonin suppresses metastasis in colon cancer cells via inhibition of TMPRSS4 mediated EMT.


Asunto(s)
Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Melatonina , Proteínas de la Membrana/antagonistas & inhibidores , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Melatonina/farmacología , Serina , Serina Endopeptidasas
17.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33808235

RESUMEN

Biocompatible nanoparticles (NPs) containing polymers, lipids (liposomes and micelles), dendrimers, ferritin, carbon nanotubes, quantum dots, ceramic, magnetic materials, and gold/silver have contributed to imaging diagnosis and targeted cancer therapy. However, only some NP drugs, including Doxil® (liposome-encapsulated doxorubicin), Abraxane® (albumin-bound paclitaxel), and Oncaspar® (PEG-Asparaginase), have emerged on the pharmaceutical market to date. By contrast, several phytochemicals that were found to be effective in cultured cancer cells and animal studies have not shown significant efficacy in humans due to poor bioavailability and absorption, rapid clearance, resistance, and toxicity. Research to overcome these drawbacks by using phytochemical NPs remains in the early stages of clinical translation. Thus, in the current review, we discuss the progress in nanotechnology, research milestones, the molecular mechanisms of phytochemicals encapsulated in NPs, and clinical implications. Several challenges that must be overcome and future research perspectives are also described.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Nanopartículas/química , Nanotecnología/métodos , Neoplasias/tratamiento farmacológico , Fitoquímicos/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Humanos , Sistema Mononuclear Fagocítico/efectos de los fármacos , Nanopartículas/administración & dosificación , Nanopartículas/uso terapéutico , Nanotubos de Carbono , Fitoquímicos/administración & dosificación , Puntos Cuánticos
18.
Phytother Res ; 35(7): 3812-3820, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33856720

RESUMEN

Since the AKT/mammalian target of rapamycin (mTOR)/c-Myc signaling plays a pivotal role in the modulation of aerobic glycolysis and tumor growth, in the present study, the role of AKT/mTOR/c-Myc signaling in the apoptotic effect of Compound K (CK), an active ginseng saponin metabolite, was explored in HepG2 and Huh7 human hepatocellular carcinoma cells (HCCs). Here, CK exerted significant cytotoxicity, increased sub-G1, and attenuated the expression of pro-Poly (ADP-ribose) polymerase (pro-PARP) and Pro-cysteine aspartyl-specific protease (pro-caspase3) in HepG2 and Huh7 cells. Consistently, CK suppressed AKT/mTOR/c-Myc and their downstreams such as Hexokinase 2 (HK2) and pyruvate kinase isozymes M2 (PKM2) in HepG2 and Huh7 cells. Additionally, CK reduced c-Myc stability in the presence or absence of cycloheximide in HepG2 cells. Furthermore, AKT inhibitor LY294002 blocked the expression of p-AKT, c-Myc, HK2, PKM2, and pro-cas3 in HepG2 cells. Pyruvate blocked the ability of CK to inhibit p-AKT, p-mTOR, HK2, and pro-Cas3 in treated HepG2 cells. Overall, these findings provide evidence that CK induces apoptosis via inhibition of glycolysis and AKT/mTOR/c-Myc signaling in HCC cells as a potent anticancer candidate for liver cancer clinical translation.


Asunto(s)
Carcinoma Hepatocelular , Ginsenósidos/farmacología , Neoplasias Hepáticas , Transducción de Señal , Apoptosis , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Glucólisis , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
19.
Semin Cancer Biol ; 68: 164-174, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-31883914

RESUMEN

Though limited success through chemotherapy, radiotherapy and surgery has been obtained for efficient cancer therapy for modern decades, cancers are still considered high burden to human health worldwide to date. Recently repurposing drugs are attractive with lower cost and shorter time compared to classical drug discovery, just as Metformin from Galega officinalis, originally approved for treating Type 2 diabetes by FDA, is globally valued at millions of US dollars for cancer therapy. As most previous reviews focused on FDA approved drugs and synthetic agents, current review discussed the anticancer potential of phytochemicals originally approved for treatment of cardiovascular diseases, diabetes, infectious diarrhea, depression and malaria with their molecular mechanisms and efficacies and suggested future research perspectives.


Asunto(s)
Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Reposicionamiento de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Fitoquímicos/uso terapéutico , Animales , Humanos
20.
Phytother Res ; 35(2): 898-907, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32822082

RESUMEN

Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub-G1 population, and increased the cleavage of Poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti-apopotic genes such as B-cell lymphoma 2 (Bcl-2) and inhibitors of apoptosis proteins (c-IAP) in HeLa and Caski cells. Furthermore, LA-inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro-PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro-PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA-induced apoptosis in cervical cancers.


Asunto(s)
Ácidos Carboxílicos/efectos adversos , Proteínas de Choque Térmico HSP27/genética , Naftalenos/efectos adversos , Neoplasias del Cuello Uterino/fisiopatología , Apoptosis , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Proteínas de Choque Térmico HSP27/metabolismo , Células HeLa , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal
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